A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs.
Maintenance of TELOMERE length. During DNA REPLICATION, chromosome ends loose some of their telomere sequence (TELOMERE SHORTENING.) Various cellular mechanism are involved in repairing, extending, and recapping the telomere ends.
An essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic CHROMOSOMES.
Proteins that specifically bind to TELOMERES. Proteins in this class include those that perform functions such as telomere capping, telomere maintenance and telomere stabilization.
A ubiquitously expressed telomere-binding protein that is present at TELOMERES throughout the CELL CYCLE. It is a suppressor of telomere elongation and may be involved in stabilization of telomere length. It is structurally different from TELOMERIC REPEAT BINDING PROTEIN 2 in that it contains acidic N-terminal amino acid residues.
A ubiquitously expressed telomere-binding protein that is present at TELOMERES throughout the cell cycle. It is a suppressor of telomere elongation and may be involved in stabilization of telomere length. It is structurally different from TELOMERIC REPEAT BINDING PROTEIN 1 in that it contains basic N-terminal amino acid residues.
The decrease in the cell's ability to proliferate with the passing of time. Each cell is programmed for a certain number of cell divisions and at the end of that time proliferation halts. The cell enters a quiescent state after which it experiences CELL DEATH via the process of APOPTOSIS.
A type of IN SITU HYBRIDIZATION in which target sequences are stained with fluorescent dye so their location and size can be determined using fluorescence microscopy. This staining is sufficiently distinct that the hybridization signal can be seen both in metaphase spreads and in interphase nuclei.
A predominantly X-linked recessive syndrome characterized by a triad of reticular skin pigmentation, nail dystrophy and leukoplakia of mucous membranes. Oral and dental abnormalities may also be present. Complications are a predisposition to malignancy and bone marrow involvement with pancytopenia. (from Int J Paediatr Dent 2000 Dec;10(4):328-34) The X-linked form is also known as Zinsser-Cole-Engman syndrome and involves the gene which encodes a highly conserved protein called dyskerin.
A group of telomere associated proteins that interact with TRF1 PROTEIN, contain ANKYRIN REPEATS and have poly(ADP-ribose) polymerase activity.
Higher-order DNA and RNA structures formed from guanine-rich sequences. They are formed around a core of at least 2 stacked tetrads of hydrogen-bonded GUANINE bases. They can be formed from one two or four separate strands of DNA (or RNA) and can display a wide variety of topologies, which are a consequence of various combinations of strand direction, length, and sequence. (From Nucleic Acids Res. 2006;34(19):5402-15)
A genus of ciliate protozoa having a unique cursorial type of locomotion.
An increased tendency to acquire CHROMOSOME ABERRATIONS when various processes involved in chromosome replication, repair, or segregation are dysfunctional.
Structures within the nucleus of fungal cells consisting of or containing DNA, which carry genetic information essential to the cell.
White blood cells. These include granular leukocytes (BASOPHILS; EOSINOPHILS; and NEUTROPHILS) as well as non-granular leukocytes (LYMPHOCYTES and MONOCYTES).
Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.
Sequences of DNA or RNA that occur in multiple copies. There are several types: INTERSPERSED REPETITIVE SEQUENCES are copies of transposable elements (DNA TRANSPOSABLE ELEMENTS or RETROELEMENTS) dispersed throughout the genome. TERMINAL REPEAT SEQUENCES flank both ends of another sequence, for example, the long terminal repeats (LTRs) on RETROVIRUSES. Variations may be direct repeats, those occurring in the same direction, or inverted repeats, those opposite to each other in direction. TANDEM REPEAT SEQUENCES are copies which lie adjacent to each other, direct or inverted (INVERTED REPEAT SEQUENCES).
Proteins obtained from the species SACCHAROMYCES CEREVISIAE. The function of specific proteins from this organism are the subject of intense scientific interest and have been used to derive basic understanding of the functioning similar proteins in higher eukaryotes.
A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement.
Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS.
An increased tendency of the GENOME to acquire MUTATIONS when various processes involved in maintaining and replicating the genome are dysfunctional.
Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.
In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)
The gradual irreversible changes in structure and function of an organism that occur as a result of the passage of time.
A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)
A genus of ciliate protozoa having a dorsoventrally flattened body with widely spaced rows of short bristle-like cilia on the dorsal surface.
A method (first developed by E.M. Southern) for detection of DNA that has been electrophoretically separated and immobilized by blotting on nitrocellulose or other type of paper or nylon membrane followed by hybridization with labeled NUCLEIC ACID PROBES.
A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).
A set of nuclear proteins in SACCHAROMYCES CEREVISIAE that are required for the transcriptional repression of the silent mating type loci. They mediate the formation of silenced CHROMATIN and repress both transcription and recombination at other loci as well. They are comprised of 4 non-homologous, interacting proteins, Sir1p, Sir2p, Sir3p, and Sir4p. Sir2p, an NAD-dependent HISTONE DEACETYLASE, is the founding member of the family of SIRTUINS.
Deoxyribonucleic acid that makes up the genetic material of fungi.
The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.
A family of enzymes that catalyze the exonucleolytic cleavage of DNA. It includes members of the class EC 3.1.11 that produce 5'-phosphomonoesters as cleavage products.
Very long DNA molecules and associated proteins, HISTONES, and non-histone chromosomal proteins (CHROMOSOMAL PROTEINS, NON-HISTONE). Normally 46 chromosomes, including two sex chromosomes are found in the nucleus of human cells. They carry the hereditary information of the individual.
Immunologically detectable substances found in the CELL NUCLEUS.
Abnormal number or structure of chromosomes. Chromosome aberrations may result in CHROMOSOME DISORDERS.
Production of new arrangements of DNA by various mechanisms such as assortment and segregation, CROSSING OVER; GENE CONVERSION; GENETIC TRANSFORMATION; GENETIC CONJUGATION; GENETIC TRANSDUCTION; or mixed infection of viruses.
Changes in the organism associated with senescence, occurring at an accelerated rate.
The process by which a DNA molecule is duplicated.
Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.
Proteins that control the CELL DIVISION CYCLE. This family of proteins includes a wide variety of classes, including CYCLIN-DEPENDENT KINASES, mitogen-activated kinases, CYCLINS, and PHOSPHOPROTEIN PHOSPHATASES as well as their putative substrates such as chromatin-associated proteins, CYTOSKELETAL PROTEINS, and TRANSCRIPTION FACTORS.
A DNA-binding protein that mediates DNA REPAIR of double strand breaks, and HOMOLOGOUS RECOMBINATION.
The reconstruction of a continuous two-stranded DNA molecule without mismatch from a molecule which contained damaged regions. The major repair mechanisms are excision repair, in which defective regions in one strand are excised and resynthesized using the complementary base pairing information in the intact strand; photoreactivation repair, in which the lethal and mutagenic effects of ultraviolet light are eliminated; and post-replication repair, in which the primary lesions are not repaired, but the gaps in one daughter duplex are filled in by incorporation of portions of the other (undamaged) daughter duplex. Excision repair and post-replication repair are sometimes referred to as "dark repair" because they do not require light.
A family of structurally-related DNA helicases that play an essential role in the maintenance of genome integrity. RecQ helicases were originally discovered in E COLI and are highly conserved across both prokaryotic and eukaryotic organisms. Genetic mutations that result in loss of RecQ helicase activity gives rise to disorders that are associated with CANCER predisposition and premature aging.
Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.
Individuals supplying living tissue, organs, cells, blood or blood components for transfer or transplantation to histocompatible recipients.
A bibliographic database that includes MEDLINE as its primary subset. It is produced by the National Center for Biotechnology Information (NCBI), part of the NATIONAL LIBRARY OF MEDICINE. PubMed, which is searchable through NLM's Web site, also includes access to additional citations to selected life sciences journals not in MEDLINE, and links to other resources such as the full-text of articles at participating publishers' Web sites, NCBI's molecular biology databases, and PubMed Central.
A publication issued at stated, more or less regular, intervals.
"The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing.
The premier bibliographic database of the NATIONAL LIBRARY OF MEDICINE. MEDLINE® (MEDLARS Online) is the primary subset of PUBMED and can be searched on NLM's Web site in PubMed or the NLM Gateway. MEDLINE references are indexed with MEDICAL SUBJECT HEADINGS (MeSH).
Publications in any medium issued in successive parts bearing numerical or chronological designations and intended to be continued indefinitely. (ALA Glossary of Library and Information Science, 1983, p203)

Analysis of genomic integrity and p53-dependent G1 checkpoint in telomerase-induced extended-life-span human fibroblasts. (1/4834)

Life span determination in normal human cells may be regulated by nucleoprotein structures called telomeres, the physical ends of eukaryotic chromosomes. Telomeres have been shown to be essential for chromosome stability and function and to shorten with each cell division in normal human cells in culture and with age in vivo. Reversal of telomere shortening by the forced expression of telomerase in normal cells has been shown to elongate telomeres and extend the replicative life span (H. Vaziri and S. Benchimol, Curr. Biol. 8:279-282, 1998; A. G. Bodnar et al., Science 279:349-352, 1998). Extension of the life span as a consequence of the functional inactivation of p53 is frequently associated with loss of genomic stability. Analysis of telomerase-induced extended-life-span fibroblast (TIELF) cells by G banding and spectral karyotyping indicated that forced extension of the life span by telomerase led to the transient formation of aberrant structures, which were subsequently resolved in higher passages. However, the p53-dependent G1 checkpoint was intact as assessed by functional activation of p53 protein in response to ionizing radiation and subsequent p53-mediated induction of p21(Waf1/Cip1/Sdi1). TIELF cells were not tumorigenic and had a normal DNA strand break rejoining activity and normal radiosensitivity in response to ionizing radiation.  (+info)

A telomere-independent senescence mechanism is the sole barrier to Syrian hamster cell immortalization. (2/4834)

Reactivation of telomerase and stabilization of telomeres occur simultaneously during human cell immortalization in vitro and the vast majority of human cancers possess high levels of telomerase activity. Telomerase repression in human somatic cells may therefore have evolved as a powerful resistance mechanism against immortalization, clonal evolution and malignant progression. The comparative ease with which rodent cells immortalize in vitro suggests that they have less stringent controls over replicative senescence than human cells. Here, we report that Syrian hamster dermal fibroblasts possess substantial levels of telomerase activity throughout their culture life-span, even after growth arrest in senescence. In our studies, telomerase was also detected in uncultured newborn hamster skin, in several adult tissues, and in cultured fibroblasts induced to enter the post-mitotic state irreversibly by serum withdrawal. Transfection of near-senescent dermal fibroblasts with a selectable plasmid vector expressing the SV40 T-antigen gene resulted in high-frequency single-step immortalization without the crisis typically observed during the immortalization of human cells. Collectively, these data provide an explanation for the increased susceptibility of rodent cells to immortalization (and malignant transformation) compared with their human equivalents, and provide evidence for a novel, growth factor-sensitive, mammalian senescence mechanism unrelated to telomere maintenance.  (+info)

Telomeric repeats on small polydisperse circular DNA (spcDNA) and genomic instability. (3/4834)

Small polydisperse circular DNA (spcDNA) is a heterogeneous population of extrachromosomal circular molecules present in a large variety of eukaryotic cells. Elevated amounts of total spcDNA are related to endogenous and induced genomic instability in rodent and human cells. We suggested spcDNA as a novel marker for genomic instability, and speculated that spcDNA might serve as a mutator. In this study, we examine the presence of telomeric sequences on spcDNA. We report for the first time the appearance of telomeric repeats in spcDNA molecules (tel-spcDNA) in rodent and human cells. Restriction enzyme analysis indicates that tel-spcDNA molecules harbor mostly, if not exclusively, telomeric repeats. In rodent cells, tel-spcDNA levels are higher in transformed than in normal cells and are enhanced by treatment with carcinogen. Tel-spcDNA is also detected in some human tumors and cell lines, but not in others. We suggest, that its levels in human cells may be primarily related to the amount of the chromosomal telomeric sequences. Tel-spcDNA may serve as a unique mutator, through specific mechanisms related to the telomeric repeats, which distinguish it from the total heterogeneous spcDNA population. It may affect telomere dynamics and genomic instability by clastogenic events, alterations of telomere size and sequestration of telomeric proteins.  (+info)

p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. (4/4834)

Although broken chromosomes can induce apoptosis, natural chromosome ends (telomeres) do not trigger this response. It is shown that this suppression of apoptosis involves the telomeric-repeat binding factor 2 (TRF2). Inhibition of TRF2 resulted in apoptosis in a subset of mammalian cell types. The response was mediated by p53 and the ATM (ataxia telangiectasia mutated) kinase, consistent with activation of a DNA damage checkpoint. Apoptosis was not due to rupture of dicentric chromosomes formed by end-to-end fusion, indicating that telomeres lacking TRF2 directly signal apoptosis, possibly because they resemble damaged DNA. Thus, in some cells, telomere shortening may signal cell death rather than senescence.  (+info)

Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. (5/4834)

To study the effect of continued telomere shortening on chromosome stability, we have analyzed the telomere length of two individual chromosomes (chromosomes 2 and 11) in fibroblasts derived from wild-type mice and from mice lacking the mouse telomerase RNA (mTER) gene using quantitative fluorescence in situ hybridization. Telomere length at both chromosomes decreased with increasing generations of mTER-/- mice. At the 6th mouse generation, this telomere shortening resulted in significantly shorter chromosome 2 telomeres than the average telomere length of all chromosomes. Interestingly, the most frequent fusions found in mTER-/- cells were homologous fusions involving chromosome 2. Immortal cultures derived from the primary mTER-/- cells showed a dramatic accumulation of fusions and translocations, revealing that continued growth in the absence of telomerase is a potent inducer of chromosomal instability. Chromosomes 2 and 11 were frequently involved in these abnormalities suggesting that, in the absence of telomerase, chromosomal instability is determined in part by chromosome-specific telomere length. At various points during the growth of the immortal mTER-/- cells, telomere length was stabilized in a chromosome-specific man-ner. This telomere-maintenance in the absence of telomerase could provide the basis for the ability of mTER-/- cells to grow indefinitely and form tumors.  (+info)

Telomere loss in somatic cells of Drosophila causes cell cycle arrest and apoptosis. (6/4834)

Checkpoint mechanisms that respond to DNA damage in the mitotic cell cycle are necessary to maintain the fidelity of chromosome transmission. These mechanisms must be able to distinguish the normal telomeres of linear chromosomes from double-strand break damage. However, on several occasions, Drosophila chromosomes that lack their normal telomeric DNA have been recovered, raising the issue of whether Drosophila is able to distinguish telomeric termini from nontelomeric breaks. We used site-specific recombination on a dispensable chromosome to induce the formation of a dicentric chromosome and an acentric, telomere-bearing, chromosome fragment in somatic cells of Drosophila melanogaster. The acentric fragment is lost when cells divide and the dicentric breaks, transmitting a chromosome that has lost a telomere to each daughter cell. In the eye imaginal disc, cells with a newly broken chromosome initially experience mitotic arrest and then undergo apoptosis when cells are induced to divide as the eye differentiates. Therefore, Drosophila cells can detect and respond to a single broken chromosome. It follows that transmissible chromosomes lacking normal telomeric DNA nonetheless must possess functional telomeres. We conclude that Drosophila telomeres can be established and maintained by a mechanism that does not rely on the terminal DNA sequence.  (+info)

Telomere shortening in mTR-/- embryos is associated with failure to close the neural tube. (7/4834)

Mice genetically deficient for the telomerase RNA (mTR) can be propagated for only a limited number of generations. In particular, mTR-/- mice of a mixed C57BL6/129Sv genetic background are infertile at the sixth generation and show serious hematopoietic defects. Here, we show that a percentage of mTR-/- embryos do not develop normally and fail to close the neural tube, preferentially at the forebrain and midbrain. The penetrance of this defect increases with the generation number, with 30% of the mTR-/- embryos from the fifth generation showing the phenotype. Moreover, mTR-/- kindreds in a pure C57BL6 background are only viable up to the fourth generation and also show defects in the closing of the neural tube. Cells derived from mTR-/- embryos that fail to close the neural tube have significantly shorter telomeres and decreased viability than their mTR-/- littermates with a closed neural tube, suggesting that the neural tube defect is a consequence of the loss of telomere function. The fact that the main defect detected in mTR-/- embryos is in the closing of the neural tube, suggests that this developmental process is among the most sensitive to telomere loss and chromosomal instability.  (+info)

Generation and characterization of human smooth muscle cell lines derived from atherosclerotic plaque. (8/4834)

The study of atherogenesis in humans has been restricted by the limited availability and brief in vitro life span of plaque smooth muscle cells (SMCs). We describe plaque SMC lines with extended life spans generated by the expression of the human papillomavirus (HPV)-16 E6 and E7 genes, which has been shown to extend the life span of normal adult human aortic SMCs. Resulting cell lines (pdSMC1A and 2) demonstrated at least 10-fold increases in life span; pdSMC1A became immortal. The SMC identity of both pdSMC lines was confirmed by SM22 mRNA expression. pdSMC2 were generally diploid but with various structural and numerical alterations; pdSMC1A demonstrated several chromosomal abnormalities, most commonly -Y, +7, -13, anomalies previously reported in both primary pdSMCs and atherosclerotic tissue. Confluent pdSMC2 appeared grossly similar to HPV-16 E6/E7-expressing normal adult aortic SMCs (AASMCs), exhibiting typical SMC morphology/growth patterns; pdSMC1A displayed irregular cell shape/organization with numerous mitotic figures. Dedifferentiation to a synthetic/proliferative phenotype has been hypothesized as a critical step in atherogenesis, because rat neonatal SMCs and adult intimal SMCs exhibit similar gene expression patterns. To confirm that our pdSMC lines likewise express this apparent plaque phenotype, osteopontin, platelet-derived growth factor B, and elastin mRNA levels were determined in pdSMC1A, pdSMC2, and AASMCs. However, no significant increases in osteopontin or platelet-derived growth factor B expression levels were observed in either pdSMC compared with AASMCs. pdSMC2 alone expressed high levels of elastin mRNA. Lower levels of SM22 mRNA in pdSMC1A suggested greater dedifferentiation and/or additional population doublings in pdSMC1A relative to pdSMC2. Both pdSMC lines (particularly 1A) demonstrated high message levels for matrix Gla protein, previously reported to be highly expressed by human neointimal SMCs in vitro. These results describe 2 novel plaque cell lines exhibiting various features of plaque SMC biology; pdSMC2 may represent an earlier plaque SMC phenotype, whereas pdSMC1A may be representative of cells comprising an advanced atherosclerotic lesion.  (+info)

Using in situ hybridisation, we identified interstitial telomeric sequences in seven chromosomal translocations present in normal and in syndromic subjects. Telomeric sequences were also found at the centromeric ends of a 4p and a 4q caused by centric fission of one chromosome 4. We found that rearrangements leading to interstitial telomeric sequences were of three types: (1) termino-terminal rearrangements with fusion of the telomeres of two chromosomes, of which we report one case; (2) rearrangements in which an acentric fragment of one chromosome fuses to the telomere of another chromosome. We describe four cases of Prader-Willi syndrome with the 15q1-qter transposed to the telomeric repeats of different recipient chromosomes; (3) telomere-centromere rearrangements in which telomeric sequences of one chromosome fuse with the centromere of another chromosome. We describe two examples of these rearrangements in which not only telomeric sequences but also remnants of alphoid sequences were found ...
Figure 1. Telomere-specific FISH in prostate adenocarcinomas. A-D, examples of telomere length and cell-to-cell variability in telomere length in malignant and benign prostate tissue from men in the HPFS who were surgically treated for clinically localized prostate cancer. A, this case has strikingly variable telomere signals among the cancer cells. B, this case has extremely short telomere signals and low variability in telomere length from cancer cell to cancer cell. C, this case has weak telomere signals in the CAS cells. D, this case has strong telomere signals in CAS cells. In all of the images, the DNA is stained with DAPI (blue) and telomere DNA is stained with the Cy3-labeled telomere-specific peptide nucleic acid probe (red). Of note, the centromere DNA, stained with the FITC-labeled centromere-specific peptide nucleic acid probe, has been omitted from the image to emphasize the differences in the telomere lengths. In all panels, the asterisks highlight the cancer cells and the arrows ...
Previously, we observed that heterochromatic 4 and Y chromosomes that had experienced breakage in the male germline were frequently transmitted to progeny. Their behavior suggested that they carried functional telomeres. Here we show that efficient healing by de novo telomere addition is not unique to heterochromatic breaks. ...
Telomeres, the physical ends of chromosomes, play an important role in preserving genomic integrity. This protection is supported by telomere binding proteins collectively known as the shelterin complex. The shelterin complex protects chromosome ends by suppressing DNA damage response and acting as a regulator of telomere length maintenance by telomerase, an enzyme that elongates telomeres. Telomere dysfunction manifests in different forms including chromosomal end-to-end fusion, telomere shortening and p53-dependent apoptosis and/or senescence. An important shelterin-associated protein with critical role in telomere protection in human and mouse cells is the catalytic subunit of DNA-protein kinase (DNA-PKcs). DNA-PKcs deficiency in mouse cells results in elevated levels of spontaneous telomeric fusion, a marker of telomere dysfunction, but does not cause telomere length shortening. Similarly, inhibition of DNA-PKcs with chemical inhibitor, IC86621, prevents chromosomal end protection through mechanism
Telomeres are the outermost parts of linear chromosomes. They consist of tandemly repeated non-coding short nucleotide sequences (TTAGGG in all vertebrates), in humans spanning over the last 2 to 15 kilobase pairs of the chromosome. Due to the end-replication problem, telomeres shorten with each cellular division. A critically short telomere will trigger the cell to enter a state of cellular senescence or to apoptose. The rate of telomere shortening can be accelerated by factors such as oxidative stress and inflammation. Taken together, this contributed to making telomere length a candidate biomarker of health and aging. Studies have shown that leukocyte telomere length progressively shortens with age, and that it independent of age is associated with age-related morbidity, lifestyle factors, and mortality. This thesis was aimed at exploring the relationships of leukocyte telomere length with various functional and structural attributes of the brain.. In Paper I, telomere length was shown to be ...
Background: Telomere length dysregulation plays a major role in cancer development and aging. Telomeres are maintained by a group of specialized genes known as shelterin and shelterin-associated proteins. In breast cancer lines it has been shown that shelterin proteins are dysregulated thereby affecting the telomere stability and contributing to the neoplastic conversion of the mammary epithelial cells. Interestingly, the regulation of some of the shelterin genes is thought to be controlled epigenetically. Methods and Results: In this study, we set out to measure the effect of increased shelterin gene expression on telomere length in breast cancer cell line 21NT treated with 5-aza-2-deoxycytidine (5-aza-CdR) using known telomere length assays. We measured telomere lengths using: Telomere Restriction Fragment length (TRF), absolute quantitative-PCR and cytogenetic Interphase Quantitative Fluorescent in situ Hybridization (iQ-FISH). We found that non-cytotoxic levels of 5-aza-CdR affect telomere ...
The SNP rs398652 on 14q21 and several other promising genetic variants were associated in our GWAS with telomere length in leukocytes. We then found that rs398652 was also associated with reduced bladder cancer risk. This SNP is located within the region of 14q that has a high linkage with leukocyte telomere length and is fewer than 450 kb from a microsatellite marker (D14S285) shown to have a very high logarithm (base 10) of odds (LOD) of approximately 3.5 for linkage with telomere length in a previous genetic linkage analysis (27). Furthermore, our mediation analysis to dissect the relationship between rs398652, telomere length, and bladder cancer risk suggests that the association of this SNP with bladder cancer is partially mediated by telomere length.. Telomere shortening and telomerase activation are critical early events of tumorigenesis. Results from a number of epidemiologic studies suggest that shorter telomere length in leukocytes is associated with increased cancer risks for several ...
Human telomeres can be maintained by the enzyme telomerase, which catalyses the addition of telomere repeats, or by the Alternative Lengthening of Telomeres (ALT) mechanism, which is recombination based. Recently, knockout mouse cell lines have indicated that epigenetic modifications associated with telomeric and subtelomeric chromatin, including DNA methylation, Histone 3 Lysine 9 (H31K9) trimethylation and Histone 4 Lysine 20 (H4K20) trimethylation, play an important role in influencing the choice of telomere maintenance mechanism. In this thesis, the levels of these modifications were studied in telomeric chromatin and in the telomere adjacent chromatin of the short arm of the human sex chromosomes (XpYp) in a panel of six human cell lines utilising different telomere maintenance mechanisms. In marked contrast to mouse models, no relationship was found between the level of any of these modifications and telomere maintenance pathway. This may indicate that the role such marks play at telomeres ...
The protective caps on chromosome ends - known as telomeres - consist of DNA and associated proteins that are essential for chromosome integrity. A fundamental part of ensuring proper telomere function is maintaining adequate length of the telomeric DNA tract. Telomeric repeat sequences are synthesized by the telomerase reverse transcriptase, and, as such, telomerase is a central player in the maintenance of steady-state telomere length. Evidence from both yeast and mammals suggests that telomere-associated proteins positively or negatively control access of telomerase to the chromosome terminus. In yeast, positive regulation of telomerase access appears to be achieved through recruitment of the enzyme by the end-binding protein Cdc13p. In contrast, duplex-DNA-binding proteins assembled along the telomeric tract exert a feedback system that negatively modulates telomere length by limiting the action of telomerase. In mammalian cells, and perhaps also in yeast, binding of these proteins probably ...
The CDC13 gene has previously been implicated in the maintenance of telomere integrity in Saccharomyces cerevisiae. With the use of two classes of mutations, here it is shown that CDC13 has two discrete roles at the telomere. The cdc13-2est mutation perturbs a function required in vivo for telomerase regulation but not in vitro for enzyme activity, whereas cdc13-1ts defines a separate essential role at the telomere. In vitro, purified Cdc13p binds to single-strand yeast telomeric DNA. Therefore, Cdc13p is a telomere-binding protein required to protect the telomere and mediate access of telomerase to the chromosomal terminus.. ...
Replication-based telomere shortening during lifetime is species- and tissue-specific, however, its impact on healthy aging is unclear. In particular, the contribution of telomere truncation to the aging process of the CNS, where replicative senescence alone fails to explain organ aging due to low to absent mitotic activity of intrinsic populations, is undefined. Here, we assessed changes in relative telomere length in non-replicative and replicative neural brain populations and telomerase activity as a function of aging in C57BL/6 mice. Telomeres in neural cells and sub-selected neurons shortened with aging in a cell cycle-dependent and -independent manner, with preponderance in replicative moieties, implying that proliferation accelerates, but is not prerequisite for telomere shortening. Consistent with this telomere erosion, telomerase activity and nuclear TERT protein were not induced with aging. Knockdown of the Rela subunit of NF-κB, which controls both telomerase enzyme and subcellular
Replication-based telomere shortening during lifetime is species- and tissue-specific, however, its impact on healthy aging is unclear. In particular, the contribution of telomere truncation to the aging process of the CNS, where replicative senescence alone fails to explain organ aging due to low to absent mitotic activity of intrinsic populations, is undefined. Here, we assessed changes in relative telomere length in non-replicative and replicative neural brain populations and telomerase activity as a function of aging in C57BL/6 mice. Telomeres in neural cells and sub-selected neurons shortened with aging in a cell cycle-dependent and -independent manner, with preponderance in replicative moieties, implying that proliferation accelerates, but is not prerequisite for telomere shortening. Consistent with this telomere erosion, telomerase activity and nuclear TERT protein were not induced with aging. Knockdown of the Rela subunit of NF-κB, which controls both telomerase enzyme and subcellular
Telomeres are the ends of eukaryotic chromosomes, consisting of consecutive short repeats that protect chromosome ends from degradation. Telomeres shorten with each cell division, leading to replicative cell senescence. Deregulation of telomere length homeostasis is associated with the development of various age-related diseases and cancers. A number of experimental techniques exist for telomere length measurement; however, until recently, the absence of tools for extracting telomere lengths...
a) Mammalian telomeres consist of tandem repeats of the TTAGGG sequence that are bound by the shelterin-telosome protein complex. Adjacent to telomeres are the subtelomeric regions, which are also rich in repetitive DNA. (b) In addition to shelterin, mammalian telomeres also contain nucleosomes that show histone modifications characteristic of heterochromatin domains. In addition, subtelomeric DNA is heavily methylated. These chromatin modifications at telomeres and subtelomeres have been shown to negatively regulate telomere length and telomere recombination. TriM, trimethyl. Image and legend from Telomere length, stem cells and aging.. You can also have a look at the diagrams related to telomere extension in my 2011 blog entry The epigenetic regulation of telomeres.. Shortened telomeres is only one of a number of factors that can contribute to cellular senescence, and may often be a downstream effect of such factors.. Apostles of telomere-extending would lead us to believe that cell ...
Newborn telomere length sets telomere length for later life. At birth, telomere length is highly variable among newborns and the environmental factors during in utero life for this observation remain largely unidentified. Obesity during pregnancy might reflect an adverse nutritional status affecting pregnancy and offspring outcomes, but the association of maternal pre-pregnancy body mass index (BMI) with newborn telomere length, as a mechanism of maternal obesity, on the next generation has not been addressed. Average relative telomere lengths were measured in cord blood (n = 743) and placental tissue (n = 702) samples using a quantitative real-time PCR method from newborns from the ENVIRONAGE birth cohort in Belgium. By using univariate and multivariable adjusted linear regression models we addressed the associations between pre-pregnancy BMI and cord blood and placental telomere lengths. Maternal age was 29.1 years (range, 17-44) and mean (SD) pre-pregnancy BMI was 24.1 (4.1) kg/m2. Decline in newborn
Almost 12 years ago, an evolutionary theory based on intergenerational telomere erosion was introduced [8] and was widely covered by the press [11, 12]. In 2011, based on published data on human telomere length inheritance, I refined my theoretical framework and located the source of human intergenerational telomere erosion in the female germline [6, 7, 10]. According to this model, telomeres in the testes of elderly males are longer than those in young males because the seniors are members of a previous generation (=birth-cohort effect) and therefore skipped, on average, one female-based intergenerational telomere loss. In 2014, I further developed the model of telomere-driven macroevolution and presented a complete biological framework for the old European model of saltatory evolution of nonadaptive characters [6].. In agreement with this theoretical model, a high-profile study, published in the August issue of Aging Cell in 2015, finally confirmed the long-awaited birth-cohort effect on ...
Telomere length analysis of donor-derived bone marrow cells (Fig. 3) and HSCs (Fig. 4) shows substantial telomere shortening during serial HSC transplantation. The difference in mean TRF length (ΔTRF) of bone marrow cells after one round of HSC transplantation is ∼1.5 kb (Fig. 3 B). This agrees reasonably well with the predicted reduction in telomere size assuming that ΔTRF is mainly due to the minimum number of extra population doublings (∼12-13) required for expansion of the fraction of the transplanted HSC population which engraft to the size of the HSC pool in adult mice (∼3-5 × 104 cells; references 3, 4), and that the rate of telomere shortening during division of the transplanted HSCs is 50-100 bp per population doubling, as observed for other mouse cells 14,39,40. However, the extent of telomere shortening during the second round of HSC transplantation (ΔTRF ≈ 5.5 kb) is considerably greater than ΔTRF during the first round of transplantation (Fig. 3). One possible ...
The results described in this study provided evidences that SYUIQ5, a Gquadruplex ligand, potently inhibited the proliferation and induced telomere DNA damage and autophagy in CNE2 and HeLa cancer cells in vitro. TRF2 delocalized from telomeres after SYUIQ5 treatment and was further degraded by proteasomes. In addition, overexpression of TRF2 prevented SYUIQ5-mediated cell death. ATM was also activated and involved in SYUIQ-5-induced telomere DNA damage response and autophagy. Furthermore, ATG5 knockdown attenuated the cytotoxicity of SYUIQ-5 in CNE2 and HeLa cells.. Telomeres are capable of forming guanine quadruplex (G4) structures on the G-rich strand, and the ligands that interact with G-quadruplex are recognized as promising anticancer agents by interfering with telomere conformation and telomere elongation. These compounds were first evaluated as telomerase inhibitors and induced telomere shortening and senescence. Recently, it was observed that G-quadruplex ligands induced a short-term ...
Debido al estado altamente heterocromatinizado del telómero se pensaba que el final de los cromosomas no era transcrito. Sin embargo, hace una década se demostró que los telómeros se transcriben en una familia de lncRNAs denominados Telomeric repeat-containing RNA o TERRA. En los últimos años, un gran número de funciones diferentes han sido asociadas a estos transcritos. Sin embargo, la falta de modelos genéticos KO para TERRA ha impedido confirmar estas funciones en sistemas celulares. La falta de modelos se debe mayoritariamente a que su origen subtelomérico no está claro. En humanos, los estudios más recientes han propuesto que TERRA se podría transcribir de 18 loci diferentes, dificultando en gran medida la generación de células KO para TERRA. Uno de los principales objetivos de mi tesis, ha sido identificar los posibles loci de TERRA humanos, con el objetivo de generar células humanas KO para TERRA. Primero evaluamos los 18 loci previamente descritos, encontrando que el 80% ...
In human cells, homologous recombination (HR) provides an accurate mechanism for the repair of DNA double-strand breaks caused by replication fork breakdown or DNA damaging agents. HR also plays a role in the maintenance of eukaryotic telomeres; cells defective in the recombinational repair proteins RAD51D or RAD54 exhibit telomere shortening and end-to-end chromosome fusions. Here we discuss the way in which HR contributes to telomere protection and elongation in mammalian cells. Understanding the mechanisms by which HR promotes telomere maintenance has important implications for genomic stability and tumorigenesis.
Telomeres are complex nucleoprotein structures that protect the extremities of linear chromosomes. Telomere replication is a major challenge because many obstacles to the progression of the replication fork are concentrated at the ends of the chromosomes. This is known as the telomere replication problem. In this article, different and new aspects of telomere replication, that can threaten the integrity of telomeres, will be reviewed. In particular, we will focus on the functions of shelterin and the replisome for the preservation of telomere integrity
4. The Curious Case of Skeletal Muscle Telomere Biology in Humans Skeletal muscle has unique telomere biology when compared to other tissues. Skeletal muscle consists of a syncytium of multinucleated muscle fibers that are postmitotic; thus, telomere length should remain stable in this population of nuclei, with the rare exception of DNA damaging stimuli [89]. In addition to myonuclei, single-nucleated populations of cells, of which the best described are satellite cells, also populate skeletal muscle [90]. Satellite cells are muscle precursor cells (i.e., adult stem cells) that are quiescent unless induced to divide by external stressors, such as contraction-induced or injury-induced muscle damage [90]. When induced to divide, satellite cells divide asymmetrically, with one daughter cell incorporating into the damaged muscle fiber and the other daughter cell returning to replenish the satellite cell pool [90]. Skeletal muscle telomere dogma states that when a muscle precursor cell is induced to ...
It is not the length of telomeres per se that protects against loss of chromosome end function, but the ability to maintain sufficient length to form a functional telomere cap. Although equilibrium telomere lengths vary dramatically between yeast, mice and humans, they share a dosage-sensitive balance between telomere loss and replenishment. In heterozygous mTert mice that have been bred for many generations, we propose that initial telomere attrition followed by eventual recovery reflects such a length-dependent equilibrium. In S. cerevisiae and humans, long telomeres inhibit telomerase access owing to cis-inhibition by telomere-bound factors such as Rif1/Rif2 and TRF1/TRF2, respectively (Smogorzewska and de Lange, 2004; Hug and Lingner, 2006). Once telomeres become short, the dosage of telomere-bound factors is reduced, leading to loss of cis-inhibition and a switch to a telomerase-extendible state (Smogorzewska and de Lange, 2004; Hug and Lingner, 2006). Upon telomere shortening, murine cells ...
We measured the effects of long-term NRTI and NNRTI exposure on telomere length maintenance using the HT29 human colorectal adenocarcinoma cell model (Table 2). HT29 has robust telomerase activities, as measured by the PCR-based telomerase activity assay [31]. HT29 cells were treated with a minimum of two concentrations of NRTIs or NNRTIs. Cell proliferation and growth rate was monitored continuously. Long-term treatment of HT29 cells with AZT is known to cause telomere length attrition [9,10,11,13]. Using the terminal restriction fragment (TRF) assay, we confirmed substantial inhibitory effects of AZT on telomere length maintenance in HT29 cells (Figure 6A and 6B). Mean telomere length was determined as a weighted average with reference to DNA standards. Figure 7. Continuous treatment of HT29 cells with the adenosine analogs TDF and ddI causes observable telomere shortening. A. TRF blots of untreated (left), TDF-treated (right) HT29 cells. PDL at which TRF was analyzed is shown above each lane. ...
Telomeres are ribonucleoprotein structures at the end of chromosomes composed of telomeric DNA, specific-binding proteins and noncoding RNA (TERRA). Despite their importance in preventing chromosome instability, little is known about the crosstalk between these three elements during the formation of the germ line. Here, we provide evidence that both TERRA and the telomerase enzymatic subunit (TERT) are components of telomeres in mammalian germ cells. We found that TERRA co-localizes with telomeres during mammalian meiosis and that its expression progressively increases during spermatogenesis, until the beginning of spermiogenesis. While both TERRA levels and distribution would be regulated in a gender-specific manner, telomere-TERT co-localization appears to be regulated based on species-specific characteristics of the telomeric structure. Moreover, we found that TERT localization at telomeres is maintained all through spermatogenesis as a structural component without affecting telomere ...
Single-stranded DNA-dependent ATP-dependent helicase. Involved in non-homologous end joining (NHEJ) DNA double strand break repair. DNA-binding is sequence-independent but has a high affinity to nicks in double-stranded DNA and to the ends of duplex DNA. Binds to naturally occurring chromosomal ends, and therefore provides chromosomal end protection. Appears to have a role in recruitment of telomerase and CDC13 to the telomere and the subsequent telomere elongation. Required also for telomere recombination to repair telomeric ends in the absence of telomerase. KU70, of the KU70/KU80 heterodimer, binds to the stem loop of TLC1, the RNA component of telomerase. Involved in telomere maintenance. Interacts with telomeric repeats and subtelomeric sequences thereby controlling telomere length and protecting against subtelomeric rearrangement. Maintains telomeric chromatin, which is involved in silencing the expression of genes located at the telomere. Required for mating-type switching.
One of the factors limiting indefinite proliferation of somatic cells is telomere length [1], [2]. Indeed, the inability to fully replicate both strands of a linear DNA molecule is expected to lead to gradual shortening of telomeres in cells that do not express telomerase. Telomere shortening may be even more severe, if the replication machinery fails to reach the telomeric end. Indeed, the highly repetitive primary structure of telomeres [3], the presence of G‐quadruplexes [4], DNA-RNA hybrids [5], [6], and T‐loops [7], as well as the extensive telomeric heterochromatinization [8], challenge the process of terminal DNA replication and make telomeres prone to fork collapse, similar to common fragile sites [9], [10]. Fork collapse within a telomere is unlikely to be resolved by incoming forks or dormant forks, since human telomeres are thought to be devoid of replication origins. Instead, telomere replication is normally dependent on a single origin, located at the subtelomeric regions [11]. ...
One of the factors limiting indefinite proliferation of somatic cells is telomere length [1], [2]. Indeed, the inability to fully replicate both strands of a linear DNA molecule is expected to lead to gradual shortening of telomeres in cells that do not express telomerase. Telomere shortening may be even more severe, if the replication machinery fails to reach the telomeric end. Indeed, the highly repetitive primary structure of telomeres [3], the presence of G‐quadruplexes [4], DNA-RNA hybrids [5], [6], and T‐loops [7], as well as the extensive telomeric heterochromatinization [8], challenge the process of terminal DNA replication and make telomeres prone to fork collapse, similar to common fragile sites [9], [10]. Fork collapse within a telomere is unlikely to be resolved by incoming forks or dormant forks, since human telomeres are thought to be devoid of replication origins. Instead, telomere replication is normally dependent on a single origin, located at the subtelomeric regions [11]. ...
The TeloYears test is not intended for screening, diagnosing, treating or preventing diseases or medical conditions. The TeloYears genetic test may indicate the possibility of identifying a rare telomere syndrome associated with extremely shorter or longer average telomere length (ATL). In these rare cases, further testing and consultation with a doctor to rule in or rule out a telomere syndrome is recommended. The test is available for individuals between the ages of 20 to 80 within the United States, except for the states of Maryland and New York. The information provided by the TeloYears test should not be used to replace medically appropriate screening tests recommended based upon actual age or other risk factors, nor should the information be used to make decisions about diagnosis or treatment of diseases or medical conditions. The Telomere Diagnostics lab is regulated under the Clinical Laboratory improvement Amendments of 1988 (CLIA) as qualified to perform high complexity clinical ...
Telomeres are specific nucleoprotein structures at the ends of eukaryotic chromosomes. Telomeres and telomere-associated proteins maintain genome stability by protecting the ends of chromosomes from fusion and degradation. In normal somatic cells, the length of the telomeres gradually becomes shortened with cell division. In tumor cells, the shortening of telomeres length is accelerated under the increased proliferation pressure. However, it will be maintained at an extremely short length as the result of activation of telomerase. Significantly shortened telomeres, activation of telomerase, and altered expression of telomere-associated proteins are common features of various hematologic malignancies and are related with progression or chemotherapy resistance in these diseases. In patients who have received hematopoietic stem cell transplantation (HSCT), the telomere length and the telomerase activity of the engrafted donor cells have a significant influence on HSCT outcomes. Transplantation-related
Understanding the molecular processes that drive cellular replicative senescence is critical to understanding human longevity. Much attention has focused on telomere length as a determinant of replicative capacity (1). Telomeres are nucleoprotein structures composed of species-specific tandemly repeated, G-rich DNA sequences that cap and protect chromosome ends from nucleolytic attack and degradation (2). Telomeres also conceal linear chromosome ends from inappropriate attempts at double-strand break (DSB) repair that might otherwise join chromosomes end-to-end. The preservation of natural chromosome ends and the rejoining of broken DNA ends, both of which are essential for preserving genomic integrity, rely on a common subset of proteins (3), and both decline with advancing age (4, 5).. The G-rich nature of telomeric DNA renders it susceptible to G-quadruplex formation, oxidative damage, and alkylation by electrophiles (6). Telomeres are also unique in their chromatin composition, being bound ...
The Patient Telomere Score is calculated based on the patients average telomere length in peripheral whole blood cells. This average is then compared to telomere lengths from a population sample in the same age range as the patient to determine the patients percentile score. What do the results mean to the patient and the doctor? Cellular attrition by analyzing the rate at which changes in average Telomere length occur over time. Cells are being lost and replaced. (Cellular attrition) What are the nutritional implications on telomere length and repair? An inflammatory diet, or one that increases oxidative stress, will shorten telomeres faster. This includes refined carbohydrates, fast foods, processed foods, sodas, artificial sweeteners, trans fats and saturated fats. A diet with a large amount and variety of antioxidants that improves oxidative defense and reduces oxidative stress will slow telomere shortening. Consumption of 10 servings of fresh and relatively uncooked fruits and vegetables, ...
Why is this important In embryonic cells (and some stem cells), an enzyme called telomerase rebuilds the telomere so that the cells can keep dividing. Over time, this telomerase dwindles and eventually the telomere shortens and the cell becomes inactive. In cancer cells, the telomerase enzyme keeps rebuilding telomeres long past the cells normal lifetime. The cells become immortal, endlessly dividing, resulting in a tumor. Researchers estimate that telomere maintenance activity occurs in about 90% of human cancers. But the mechanism by which this maintenance takes place is not well understood. The researchers discovered that the RNA in the telomere is regulated by a protein in the telomerase enzyme. Their discovery may thus uncover key elements of telomere function ...
TY - JOUR. T1 - Telomere length in peripheral blood leukocytes and risk of renal cell carcinoma. AU - Park, Jong Y.. AU - Luu, Hung N.. AU - Park, Hyun Y.. AU - Lin, Hui Yi. AU - Radlein, Selina. AU - Di Pietro, Giuliano. AU - Yeo, Chang Dong. AU - Kim, Seung Joon. AU - Kang, Nahyeon. AU - Antwi, Samuel. AU - Sexton, Wade J.. AU - Spiess, Philippe E.. AU - Dickinson, Shohreh. AU - Parker, Alexander. PY - 2019/1/1. Y1 - 2019/1/1. N2 - Background: Telomeres are essential for chromosomal stability and may play a key role in carcinogenesis. Telomere length is suggested as a tentative biomarker of risk for renal cell carcinoma (RCC). However, results of previous association studies between telomere length and risk for RCC are inconsistent. Methods: We evaluated RCC risk in relation to peripheral blood leukocyte telomere length using a hospital-based case-control study of 169 RCC cases and 189 controls. Cases were histologically-confirmed RCC patients who were treated at the Moffitt Cancer Center ...
An SGA approach to discover cdc13-1ts supressors. Telomeres, the DNA-protein complexes at the end of eukaryotic chromosomes, are essential for chromosomal stability. In yeast, the telomeric single-strand binding protein Cdc13p has multiple important roles related to telomere maintenance: (1) telomericcapping--protection of telomeres by forming complexes with yKu70/80 and with Stn1p/Ten1p; (2) positive regulation of telomere replication via interaction with Est1p, which is a part of telomerase; (3) negative regulation of telomerase by the recruitment of telomere elongation suppressors Stn1p and Ten1p. In an attempt to identify genes that are involved in the deleterious outcome of an absence of Cdc13p, we screened the yeast gene knock-out library for genes that could suppress the growth defect of cdc13-1 cells at 33ê C. For this purpose, we performed an SGA array experiment. We scored for the ability of double mutant haploids to grow at 33ê C. Eventually, we hoped to find the elusive genes ...
Laure Crabbe, Ramiro E. Verdun, Candy I. Haggblom, and Jan Karlseder http://sageke.sciencemag.org/cgi/content/abstract/2004/50/or22 Abstract: Science 306, 1951-1953 (2004).. Cells from Werner syndrome patients are characterized by slow growth rates, premature senescence, accelerated telomere shortening rates, and genome instability. The syndrome is caused by the loss of the RecQ helicase WRN, but the underlying molecular mechanism is unclear. Here we report that cells lacking WRN exhibit deletion of telomeres from single sister chromatids. Only telomeres replicated by lagging strand synthesis were affected, and prevention of loss of individual telomeres was dependent on the helicase activity of WRN. Telomere loss could be counteracted by telomerase activity. We propose that WRN is necessary for efficient replication of G-rich telomeric DNA, preventing telomere dysfunction and consequent genomic instability.. [Abstract/Full Text]. ...
We have isolated STN1, an essential Saccharomyces cerevisiae gene, as a suppressor of the cdc13-1 mutation. A synthetic lethal interaction between a temperature-sensitive mutant allele of STN1, stn1-13, and cdc13-1 was observed. Stn1 and Cdc13 proteins displayed a physical interaction by two-hybrid analysis. As shown previously for cdc13-1, stn1-13 cells at the restrictive temperature accumulate single-stranded DNA in subtelomeric regions of the chromosomes, but to a lesser extent than cdc13-1 cells. In addition, both Cdc13 and Stn1 were found to be involved in the regulation of telomere length, mutations in STN1 or CDC13 conferring an increase in telomere size. Loss of Stn1 function activated the RAD9 and MEC3 G2/M checkpoints, therefore confirming that DNA damage is generated. We propose that Stn1 functions in telomere metabolism during late S phase in cooperation with Cdc13 ...
Telomeres, which are found at the end of eukaryotic linear chromosomes, are essential for chromosome maintenance and genomic stability (1). Mammalian telomeres are composed of repetitive d-(TTAGGG) sequences and telomere-specific shelterin complex proteins, which protect the chromosome ends from being recognized as DNA damage and preventing end-to-end chromosomal fusions (2). The shelterin proteins (TRF1, TRF2, POT1, TIN2, TPP1, and RAP1) form a protective complex that is present at telomeres throughout the cell cycle (3). Because of the end-replication problem, oxidative damage and other replication-associated end-processing events, telomeres progressively shorten with each round of DNA replication in normal somatic cells (4). The ribonucleoprotein enzyme complex telomerase counteracts telomere shortening by adding hexameric telomeric DNA (TTAGGG) repeats to the end of linear chromosomes in cancer cells but only partially counteracts progressive telomere shortening in some normal human ...
Figure 3. Mutations in STN1 result in abnormal telomere phenotypes. (A) DNA samples, prepared from PBLs of patient P1, her heterozygous father (F1), and a noncarrier sibling (S1) and patient P2, his heterozygous mother (M2), and two independent control samples (C), were analyzed by in-gel hybridization. Duplicated lanes were electrophoresed in the same gel, and then separated and hybridized to a G-rich or C-rich telomeric probe, as indicated above the panels. After native hybridization to detect single-stranded telomeric DNA (top), the gels were denatured and rehybridized with the same probes to detect the overall duplex telomeric DNA (bottom). Treatment with exonuclease I is indicated above the lanes. (B) Graphic illustration of the mean telomere length for the patients and their family members, calculated based on the following number of independent measurements of four in-gels and two Southern analyses: P1:6, M1:3, F1:3, S1:3, P2:9, M2:3, F2:1, C1:2, and C2:3. (C) Graphic illustration of the ...
Osteoarthritis (OA) and osteoporosis (OP) are associated skeletal pathologies and have as a distinct feature the abnormal reconstruction of the subchondral bone. OA and OP have been characterized as age‑related diseases and have been associated with telomere shortening and altered telomerase activity (TA). This review discusses the role of telomeres and telomerase in OA and OP pathologies and focuses on the usability of telomere length (TL) and the rate of telomere shortening as potential disease biomarkers. A number of studies have demonstrated that telomere shortening may contribute to OA and OP as an epigenetic factor. Therefore, it has been claimed that the measurement of TL of chondrocytes and/or peripheral blood cells may be an appropriate marker for the evaluation of the progression of these diseases. However, there is a need to be perform further studies with larger cohorts, with the aim of obtaining objective results and a better understanding of the association between TL, ...
POT1 is one of the six core components of the human telomeric protein complex (reviewed in de Lange, 2005). This complex is composed of TRF1, TRF2, TIN2, TPP1 (previously known as PIP1, PTOP, or TINT1), Rap1, and POT1, which are thought to fulfill the two main functions of telomeres: the recruitment and regulation of telomerase, and the protection of chromosome ends. Defects in telomere protection activate the DNA damage response, leading to a DNA damage signal and inappropriate DNA repair reactions at chromosome ends. The cell cycle arrest resulting from telomere dysfunction is thought to be responsible for the finite lifespan of human cells lacking telomerase.. The current challenge is to understand how the telomeric complex protects chromosome ends from being recognized as sites of DNA damage. One approach is to define which repair and signaling pathways are repressed at natural chromosome ends by studying the events at dysfunctional telomeres. This approach has shown that chromosome ends are ...
Acts both as a regulator of telomere function and as a transcription regulator. Involved in the regulation of telomere length and protection as a component of the shelterin complex (telosome). In contrast to other components of the shelterin complex, it is dispensible for telomere capping and does not participate in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair. Instead, it is required to negatively regulate telomere recombination and is essential for repressing homology-directed repair (HDR), which can affect telomere length. Does not bind DNA directly: recruited to telomeric double-stranded 5-TTAGGG-3 repeats via its interaction with TERF2. Independently of its function in telomeres, also acts as a transcription regulator: recruited to extratelomeric 5-TTAGGG-3 sites via its association with TERF2 or other factors, and regulates gene expression. When cytoplasmic, associates with the I-kappa-B-kinase (IKK) complex and acts as a regulator of the NF-kappa-B
Telomere attrition has been associated with age-related diseases, although causality is unclear and controversial; low-grade systemic inflammation (inflammaging) has also been implicated in age-related pathogenesis. Unpicking the relationship between aging, telomere length (TL), and inflammaging is hence essential to the understanding of aging and management of age-related diseases. This longitudinal study explored whether telomere attrition is a cause or consequence of aging and whether inflammaging explains some of the associations between TL and one marker of aging, grip strength. We studied 253 Hertfordshire Ageing Study participants at baseline and 10-year follow-up (mean age at baseline 67.1 years). Participants completed a health questionnaire and had blood samples collected for immune-endocrine and telomere analysis at both time points. Physical aging was characterized at follow-up using grip strength. Faster telomere attrition was associated with lower grip strength at follow-up (β = 0.98, p =
Depletion of hematopoietic stem cell reserves, expressed as the shortening of leukocyte telomere length (LTL), sets a limit on longevity and increases the risk...
TELOMERES are nucleoprotein complexes at the termini of linear eukaryotic chromosomes that perform a critical role in maintaining genome stability. At the DNA level, telomeres typically comprise long double-stranded tracts of a repetitive GT/CA-rich sequence, terminating in a short single-stranded 3′ overhang that corresponds to the strand bearing the G-rich repeats. A large number of proteins associate with the telomere repeats to form a structure that allows telomeres to act as caps that protect chromosome ends from degradation and illegitimate end-to-end fusions. Chromosomes are considered capped if they preserve the physical integrity of the telomere while allowing cell division to proceed (Blackburn 2000). Proteins that bind to the duplex portion of telomeres, such as TRF1 and TRF2 in mammalian cells and Rap1p in Saccharomyces cerevisiae, as well as proteins that bind the single-strand overhang, such as POT1 in mammalian cells and Cdc13p in S. cerevisiae, are essential for proper ...
Telomeres are complex DNA-protein structures located at the end of eukaryotic chromosomes. Telomere length shortens with age in all replicating somatic cells. It has been shown that tobacco smoking enhances telomere shortening in circulating lymphocytes. The present study investigated whether this effect was further amplified in smokers who develop chronic obstructive pulmonary disease.. Telomere length was determined by fluorescence in situ hybridisation in circulating lymphocytes harvested from 26 never-smokers, 24 smokers with normal lung function and 26 smokers with moderate-to-severe airflow obstruction (forced expiratory flow in one second 48±4% predicted).. In contrast to never-smokers, telomere length significantly decreased with age in smokers. There was also a dose-effect relationship between the cumulative long-life exposure to tobacco smoking (pack-yrs) and telomere length. The presence and/or severity of chronic airflow obstruction did not modify this relationship.. The results of ...
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the t(9;22) translocation. As in most cancers, short telomeres are one of the features of CML cells, and telomere shortening accentuates as the disease progresses from the chronic phase to the blastic phase. Although most individual telomeres are short, some of them are lengthened, and long individual telomeres occur non-randomly and might be associated with clonal selection. Telomerase is the main mechanism used to maintain telomere lengths, and its activity increases when CML evolves toward advanced stages. ALT might be another mechanism employed by CML cells to sustain the homeostasis of their telomere lengths and this mechanism seems predominant at the early stage of leukemogenesis. Also, telomerase and ALT might jointly act to maintain telomere lengths at the chronic phase, and as CML progresses, telomerase becomes the major mechanism. Finally, CML cells display an altered nuclear organization of their telomeres which
So, poorly functioning mitochondria lead to telomere shortening, and telomerase somehow improves mitochondrial function to prevent that shortening. This is in place of the more expected path of undoing ongoing telomere shortening by adding extra repeat sequences to the end of the telomeres - that being the better understood function of telomerase.. Damaged mitochondria are a fundamental root cause of age-related degeneration far above and beyond the matter of telomeres. If telomerase acts to improve the state of mitochondria, this might explain why telomere length correlates so well with general measures of health in the old. It might even be the case that, setting aside cancer for one moment, telomere length really isnt that important in comparison to your mitochondrial health.. This all cries out for more research - the prospect of reducing two thorny problems down to one in the development of medical technologies to repair and prevent aging is very welcome. Regardless of the outcome, efforts ...
Objective: Telomere length is associated with poorer lung health in older adults, possibly from cumulative risk factor exposure, but data are lacking in pediatric and population-based cohorts. We examined associations of telomere length with lung function in children and mid-life adults.Methods: Data were drawn from a population-based cross-sectional study of 11 to 12 year-olds and mid-life adults. Lung function was assessed by spirometric FEV1, FVC, FEV1 /FVC ratio, and MMEF25-75. Telomere length was measured by quantitative polymerase chain reaction from blood and expressed as the amount of telomeric genomic DNA to the beta-globin gene (T/S ratio). Associations of telomere length with spirometric parameters were tested by linear and logistic regression models, adjusting for potential confounders of sex, age, body mass index, socioeconomic position, physical activity, inflammation, asthma, pubertal status, and smoking.Results: Mean T/S ratio was 1.09 (n = 1206; SD 0.55) in children and 0.81 (n ...
CONTEXT: Both leukocyte telomere length and IGF-I are associated with the aging process. A previous in vitro study suggested that IGF-I may modulate telomerase activity in white blood cells, but little is known whether these two systems interact in vivo. PATIENTS AND METHODS: Leukocyte telomere length was determined using a quantitative PCR assay in 2744 elderly men (mean age 75.5 yr, range 69-81 yr) included in the population-based Osteoporotic Fractures in Men-Sweden study. Serum IGF-I concentration was measured using RIA. RESULTS: Subjects with a leukocyte telomere length in the lowest tertile group had lower serum IGF-I concentration than subjects in the two tertile groups with longer telomere lengths (P = 0.005). Logistic regression analyses showed that a higher serum IGF-I concentration was associated with a significantly reduced risk of having a leukocyte telomere length in the lowest tertile group and also after adjustment for multiple covariates (P , 0.01). Multivariate linear ...
Objectives: Telomere erosion, a feature of biological ageing, is implicated in a wide range of diseases. Its impact on autoimmune diseases remains unclear although autoantibodies against many telomere nucleoprotein components are prevalent in these diseases. We aimed to assess if telomere biology was abnormal in a cohort of patients with limited cutaneous systemic sclerosis (lcSSc).. Methods: Telomere lengths in peripheral blood leucocytes (PBL) were determined using Southern blotting methods in a cohort of lcSSc subjects (n = 43; age range 37-80 years) and a control population (n = 107; age range 21-65 years).. Results: Telomere lengths in lcSSc subjects were longer than controls (p,0.001), did not show age-related telomere erosion and differed significantly from age-matched controls only after 50 years of age (p,0.001).. Conclusions: This is the first report of maintenance of telomere lengths in an autoimmune disease state. These data indicate aberrant telomere biology and irregular biological ...
Abstract Bachground The premature ovarian failure (POF) is a reason of infertility that affects about 1-4% of women before age 40. The importance of telomeres length in different diseases has been explored before. This study examines the association between the relative telomere length and idiopathic POF in a group of Iranian women. Methods The blood genomic DNA was extracted from 40 idiopathic POF patients (case group) and 40 fertile women (control group). The relative telomere length (RTL) was evaluated by quantitative Real-Time PCR using specific telomeric primers. RTL was calculated as T (telomere)/S (single copy gene) ratio and compared between infertile and fertile groups. Results A strong association was considered between telomere size and idiopathic premature ovarian failure. In patients the relative telomere length showed to be significantly longer than those of control group (P , .05, 95% CI). Conclusion Our findings demonstrate a possible relationship between telomere lengthening ...
Consumption of sugar-sweetened beverages (SSBs) is linked to increased risks of metabolic disease, but the biological mechanisms underlying this association are still under investigation. Leukocyte telomere length maintenance underlies healthy cellular aging, and may provide a link between SSB consumption and risk of disease. Given the known effects of SSBs on oxidative stress and insulin resistance, we examined the associations between sugar-sweetened beverage, diet soda, and fruit juice consumption, and leukocyte telomere length in 5,309 healthy adults with no prior history of diabetes or cardiovascular disease, using data from the 1999-2002 National Health and Nutrition Surveys (NHANES). We hypothesized that beverages with high sugar content would be most detrimental to cellular aging. Leukocyte telomere length was assayed from DNA specimens collected from adult NHANES participants. Diet was assessed using 24-hour dietary recalls. Because 24-hour dietary recalls may not accurately reflect ...
Schizophrenia is a complex neurodevelopmental disorder characterized by mental dysfunction in multiple domains of the brain (46). Previous studies have shown lower telomere length in patients with schizophrenia and paranoid schizophrenia compared to control groups (47,48). Patients suffering from paranoid schizophrenia, who were under anti-psychotics medication had slightly decreased leukocyte telomere length. In addition, telomere length analysis of paranoid schizophrenic patients revealed that response to treatment influences telomere length with poor responders having the shorter telomeres (49). By contrast, other authors have shown that the poor responders had the shortest terminal restriction fragments (TRFs) which was inversely associated with age. Furthermore, Fernandez-Egea et al (19), who included both men and women, showed that the whole psychosis group had decreased telomere content compared to the control group and that both men and women had the same telomere content. However, when ...
Electrochemical behavior of the anticancer doxorubicin hydrochloride( DOX) and the interaction of DOX with human telomere DNA were investigated by cyclic voltammetry in aqueous medium using p H 6. 0 PBS buffer. The results showed that a pair of reversible oxidation- reduction peaks were observed at- 0. 585 V and- 0. 638 V in p H 6. 0 PBS buffer. There existed excellent linearities between oxidation peak current and concentration of DOX in the ranges of 0. 03- 0. 8 μmol/L and0. 8- 10 μmol/L by linear sweep voltammetric method. Detection limit( S/N = 3) was 0. 01 μmol /L. The relative standard deviations of the oxidation peak current obtained from 11 determinations of the same solutions containing 0. 5 μmol/L DOX were 3. 5%. The oxidation peak current of DOX gradually decreased with the adding of various concentrations of human telomere DNA,due to interaction of DOX with human telomere DNA. The binding ratio was calculated to be 1 ∶ 1 and the binding equilibrium constant was 1. 11 × 103 L/mol.
In this study, we identify decreased dyskerin protein levels as a novel mechanism of disease in X-linked DC. In affected individuals, despite the presence of an intact coding sequence, decreased dyskerin levels were associated with reduced hTR stability and telomere shortening. Knockdown of dyskerin levels has been previously shown to decrease hTR levels in cancer cell lines,39 40 although its consequences on telomere length have not been examined. Our data indicate that intact dyskerin levels, and not only protein sequence, are essential for in vivo telomere maintenance, and this defect is sufficient to cause premature mortality due to telomere mediated disease. In half of X-linked DC families, the mechanism of disease is not known. Our data, if replicated in larger cohorts, would suggest that quantitation of dyskerin protein levels can complement sequencing of the DKC1 gene, and decreased levels of dyskerin, measured by sensitive methods, can identify male carrier status in a subset of ...
Telomerase, the ribonucleoprotein complex involved in telomere maintenance, is composed of two main components: hTERT and hTERC. hTERT seems to be the rate-limiting factor for telomerase activity, although hTERC expression was also shown to correlate to a certain extent with telomerase reactivation. To determine whether the absence of hTERC expression could be the consequence of DNA methylation, we quantified hTERC RNA in 60 human samples (19 telomerase-negative normal tissues, nine telomerase-positive and 22 telomerase-negative tumor tissues, eight telomerase-positive and two telomerase-negative cell lines) using a quantitative dot blot on RT-PCR products. Most of the normal tissues did not express hTERC whereas, in telomerase-positive cell lines and in telomerase-positive tumor tissues, a strong up-regulation was observed, suggesting that hTERC transcription is up-regulated during tumorigenesis. The two telomerase-negative cell lines did not express hTERC. In a series of 22 telomerase-negative ...
in Anticancer Research (2008), 28(5c), 3257-3258. Telomeres consist of protein complexes and repeated TTAGGG double strand DNA sequences ended by a 3 single strand DNA of the same sequence. Progressive telomere shortening is observed in vitro upon ... [more ▼]. Telomeres consist of protein complexes and repeated TTAGGG double strand DNA sequences ended by a 3 single strand DNA of the same sequence. Progressive telomere shortening is observed in vitro upon cell divisions and with ageing in vivo. At a critical telomere length, shortened telomeres trigger a permanent growth arrest known as replicative senescence. Telomerase is an RNA-dependent DNA polymerase that extends telomeres by adding TTAGGG repeats. It consists of a functional RNA component (hTR) which serves as template and a catalytic protein (hTERT) with reverse transcriptase activity. The expression of hTERT alone is sufficient for the immortalisation of cells. Telomerase is highly expressed in tumor cells but at very low level ...
Limitless self-renewal is one of the hallmarks of cancer and is attained by telomere maintenance, essentially through telomerase (hTERT) activation. Transcriptional regulation of hTERT is believed to play a major role in telomerase activation in human cancers. The dominant interest in telomerase results from its role in cancer. The role of telomeres and telomere maintenance mechanisms is well established as a major driving force in generating chromosomal and genomic instability. Cancer cells have acquired the ability to overcome their fate of senescence via telomere length maintenance mechanisms, mainly by telomerase activation. hTERT expression is up-regulated in tumors via multiple genetic and epigenetic mechanisms including hTERT amplifications, hTERT structural variants, hTERT promoter mutations and epigenetic modifications through hTERT promoter methylation. Genetic (hTERT promoter mutations) and epigenetic (hTERT promoter methylation and miRNAs) events were shown to have clinical implications in
Telomeres, the natural ends of linear eukaryotic chromosomes, are essential for chromosome stability. Because of the nature of DNA replication, telomeres require a specialized mechanism to ensure their complete duplication. Telomeres are also capable of silencing the transcription of genes that are located near them. In order to identify genes in the budding yeast Saccharomyces cerevisiae that are important for telomere function, a screen was conducted for genes that, when expressed in high amounts, would suppress telomeric silencing. This screen lead to the identification of the gene TLC1 (telomerase component 1). TLC1 encodes the template RNA of telomerase, a ribonucleoprotein required for telomere replication in a variety of organisms. The discovery of TLC1 confirms the existence of telomerase in S. cerevisiae and may facilitate both the analysis of this enzyme and an understanding of telomere structure and function. ...
Author Summary The enzyme complex telomerase, with its two main components telomerase reverse transcriptase and telomerase RNA, plays an important role in telomere maintenance. Perturbation of telomere length regulation can ultimately result in cellular senescence (telomere shortening) and is also observed in tumor cells (increased telomere maintenance). Recent studies suggest telomerase RNAs can function independently of the telomerase complex and promote tumor development independently of telomere maintenance. Here we demonstrate that vTR, a herpesvirus-encoded telomerase RNA, serves two distinct functions in MDV-induced tumor formation. vTR has its first function early after infection, when it is part of the telomerase complex and contributes to the survival of rapidly dividing transformed cells. The second function of vTR is independent of telomerase action and essential for formation of solid lymphomas and metastasis. This latter function is likely a consequence of vTR-mediated gene regulation that
PARN encodes poly(A)-specific ribonuclease. Biallelic and monoallelic PARN variants are associated with Hoyeraal-Hreidarsson syndrome/dyskeratosis congenita and idiopathic pulmonary fibrosis (IPF), respectively. The molecular features associated with incomplete penetrance of PARN-associated IPF have not been described. We report a family with a rare missense, p.Y91C, and a novel insertion, p.(I274*), PARN variant. We found PARN p.Y91C had reduced deadenylase activity and the p.(I274*) transcript was depleted. Detailed analysis of the consequences of these variants revealed that, while PARN protein was lowest in the severely affected biallelic child who had the shortest telomeres, it was also reduced in his mother with the p.(I274*) variant but telomeres at the 50th percentile. Increased adenylation of telomerase RNA, human telomerase RNA, and certain small nucleolar RNAs, and impaired ribosomal RNA maturation were observed in cells derived from the severely affected biallelic carrier, but not in ...
Telomeres are important protein-DNA structures at the ends of linear eukaryotic chromosomes that are necessary for genome integrity. Telomeres are maintained by intermittent action of telomerase. I explored the kinetics of telomere length homeostasis in the model plant Arabidopsis thaliana by crossing wild type plants to different generations of telomerase deficient plants, and then analyzing telomere length in the resulting progeny. Unexpectedly, I found plants lacking telomerase for seven generations can lengthen telomeres when telomerase is reintroduced, but one generation is not sufficient to reestablish the telomere set point. Est1 is a non-catalytic component of the Saccharomyces cerevisiae telomerase holoenzyme. To investigate the role of Est1 in higher eukaryotes, I identified two putative Est1 homologues in Arabidopsis, AtEST1a and AtEST1b. Plants deficient in AtEST1a displayed no vegetative or reproductive defects. However, plants deficient for AtEST1b were sterile and had severe ...
TY - JOUR. T1 - Telomere length and physical performance among older people - the Helsinki Birth Cohort Study. AU - Åström, Max J.. AU - von Bonsdorff, Mikaela B.. AU - Perälä, Mia-Maria. AU - Salonen, Minna K.. AU - Rantanen, Taina. AU - Kajantie, Eero. AU - Simonen, Mika. AU - Pohjolainen, Pertti. AU - Haapanen, Markus J.. AU - Guzzardi, Maria A.. AU - Iozzo, Patricia. AU - Kautiainen, Hannu. AU - Eriksson, Johan G.. PY - 2019/10. Y1 - 2019/10. KW - 3142 Public health care science, environmental and occupational health. KW - Biomarkers. KW - Physical function. KW - Aging. KW - Epidemiology. KW - Biomarkers. KW - Physical function. KW - Aging. KW - Epidemiology. KW - MORTALITY. KW - ASSOCIATION. KW - FRAILTY. KW - BIOMARKERS. KW - DISABILITY. KW - CAPABILITY. KW - FITNESS. KW - MARKERS. KW - HEALTH. KW - BLOOD. U2 - 10.1016/j.mad.2019.111145. DO - 10.1016/j.mad.2019.111145. M3 - Article. VL - 183. JO - Mechanisms of Ageing and Development. JF - Mechanisms of Ageing and Development. SN - ...
Postdoctoral position to study telomere structure and function. A postdoctoral position is available to investigate telomere dynamics in Saccharomyces cerevisiae in the laboratory of Art Lustig at Tulane University Medical Center. We have had a long-standing fascination in telomere structure and function and are currently focusing on two broad areas: 1) The mechanisms of nucleation and inheritance of telomeric silencing (e.g. MCB 16: 2843); and 2) the mechanism of telomere size maintainence (e.g. Genes Dev. 10: 1310). Candidates should have a background in molecular biology and/or genetics. Background in yeast is preferable but not required. Interested candidates should send their c.v. either by e-mail, fax, or mail to the address listed below. Arthur J. Lustig Associate Professor Department of Biochemistry SL43 Tulane University Medical Center 1430 Tulane Avenue New Orleans, LA 70112 phone: 504-584-3688 fax: 504-584-2739 ...
Knowing that pluripotent embryonic cells are telomerase positive, we could freely draw conclusion that all of them should have similar telomeres length. However, it has been shown that the telomere length in the oocytes and blastocysts differs greatly from the telomeres in the zygote, more than it had been expected [86]. While an average oocytes telomere length has been determined as ~ 11.12 kb and a blastocysts as 12.22 kb, the average telomere length for the cleavage stage embryo is ~ 8.43 kb [87]. It is speculated that the alternative lengthening of telomeres (ALT) mechanism through chromosomal recombination in early embryo cells could yield in this discrepancy [88]. The ALT pathway has not yet been observed in human embryo cells, but it already has been shown that both mechanisms (telomerase-dependent and -independent) coexist in the same cell, which possibly could explain the differential telomeres length phenomenon in the human embryo cells [89,90]. Moreover, it has been reported that ...
The lab studies telomeres, protective elements at the ends of chromosomes that are critical for genome integrity and shorten with cell division. de Lange seeks to understand how telomeres are protected by a protein complex called shelterin, how they are replicated and maintained, and how telomere loss contributes to genome instability in cancer. The lab also studies DNA double-strand break repair with emphasis on the function of two critical DNA repair proteins, BRCA1 and 53BP1. Research in the de Lange lab focuses on human and mouse telomeres, which are made up of long arrays of double-stranded TTAGGG repeats that end in a single-stranded 3′ overhang. The lab identified a six-subunit protein complex, which they named shelterin, that specifically binds to telomeres. Using genetic approaches, de Lange and her colleagues determined the fate of telomeres lacking one or more of the six shelterin subunits. The results showed that cells lacking shelterin perceive their natural chromosome ends as ...
The human Xp/Yp telomere-junction region exhibits high levels of sequence polymorphism and linkage disequilibrium. To determine whether this is a general feature of human telomeres, we have undertaken sequence analysis at the 12q telomere and have extended the analysis at Xp/Yp. A total of 22 single-nucleotide polymorphisms (SNPs) and one 30-bp duplication were detected in the 1,870 bp adjacent to the 12q telomere. Twenty polymorphic positions were in almost complete linkage disequilibrium, creating three common diverged haplotypes accounting for 80% of 12q telomeres in the white population. A further 6% of 12q telomeres contained a 1,439-bp deletion in the DNA flanking the telomere. The remaining 13% of 12q telomeres did not amplify with the primers used (nulls). The distribution of telomere (TTAGGG) and variant repeats within 12q telomeres was hypervariable, but alleles with similar distribution patterns were associated with the same haplotype in the telomere-adjacent DNA. These data suggest ...
In recent years it has become increasingly clear that articular cartilage harbours a viable pool of progenitor cells and interest has focussed on their role during development and disease. Analysis of progenitor numbers using fluorescence-activated sorting techniques has resulted in wide-ranging estimates, which may be the result of context-dependent expression of cell surface markers. We have used a colony-forming assay to reliably determine chondroprogenitor numbers in normal and osteoarthritic cartilage where we observed a 2-fold increase in diseased tissue (P , 0.0001). Intriguingly, cell kinetic analysis of clonal isolates derived from single and multiple donors of osteoarthritic cartilage revealed the presence of a divergent progenitor subpopulation characterised by an early senescent phenotype. Divergent sub-populations displayed increased senescenceassociated β-galactosidase activity, lower average telomere lengths but retained the capacity to undergo multi-lineage differentiation. ...
Our lab is interested in telomere function, the regulation of telomere length and the biochemistry of telomerase. Telomeres are essential for both chromosome stability and for length maintenance. Telomerase is a ribonucleoprotein reverse transcriptase that synthesizes telomere repeats onto chromosome ends. Telomerase is required for telomerase length maintenance: in the absence of telomerase, telomeres shorten progressively. To understand the telomerase, we initially focused on the well characterized Tetrahymena enzyme. We extensively characterized the functional regions of the Tetrahymena telomerase RNA. Using a reconstitution system, we mapped the essential RNA functional region. To extend this analysis to mammalian telomerase we established the secondary structure of the vertebrate telomerase RNA. We cloned and sequenced telomerase RNA genes from 35 vertebrate species and determined the secondary structure using phylogenetic comparative analysis. We identified four highly conserved domains in ...
A new study reported in the press this week looks at the relationship of exercise to expression of telomerase and telomere lengths in athletes and non-athletes. Other studies on the same topic have appeared in the last year or so. My purpose here is to review these studies in the context of some earlier studies. It is not just a simple matter of the more and the harder the exercise, the better.. The 12th theory of aging in my treatise Telomere Shortening and Damage forwards the hypothesis that longer telomere lengths are likely to be correlated with longer lifespans and that keeping ones telomeres as long as possible through expression of telomerase is vital for health and longevity. I have devoted numerous blog entries to telomeres and telomerase, including most recently Timely telomerase tidbits, Breakthrough telomere research finding, and Telomere and telomerase writings. On the other hand, it is also well established that regular exercise is also strongly supportive of ...
Telomere Binding Activity (TBA), an abundant protein from Saccharomyces cerevisiae, was identified by its ability to bind to telomeric poly(C1-3A) sequence motifs. The substrate specificity of TBA has been analyzed in order to determine whether the activity binds to a unique structure assumed by the …
(2016) Biron-Shental et al. Placenta. Objective Diabetes during pregnancy causes an intrauterine environment that influences lifetime sickness of the mother and the fetus. There is a correlation between diabetes and telomere shortening; however, very little is known about telomere homeostasis in ...
In almost all eukaryotes, the task of solving the end-replication problem and counteracting telomere erosion is assigned to the telomerase enzyme complex (Greider and Blackburn, 1985). The active telomerase holoenzyme in mammalian cells exists as a dimer and consists of the telomerase reverse transcriptase (TERT), the telomerase RNA component (TERC) and dyskerin (Cohen et al., 2007). In humans, telomerase is expressed during the early stages of embryogenesis, and its expression is subsequently repressed in most somatic cells, except the male germ line, activated lymphocytes and stem cells found in certain regenerative tissues (Wright et al., 1996). Furthermore, the vast majority of human cancer cells reactivate telomerase, and are thus capable of proliferating indefinitely (Kim et al., 1994). Regulation of telomerase is primarily exerted at the level of TERT transcription. Extensive analysis of the promoter region has uncovered many transcriptional binding sites and regulatory elements, ...
Fig. 3. NHP2 mutations result in short telomeres and reduced TERC levels. (A) Telomere length measurements in 112 healthy control subjects (open circles) are plotted against age with a line of best fit. Members of families in which NHP2 mutations are segregating are shown as gray triangles (Y139H heterozygotes), a black triangle (Y139H homozygote), gray square (V126M heterozygote), gray diamond (X154R heterozygote), black diamond (V126M/X154R, compound heterozygote), and open diamond (normal sibling). (B) Age-adjusted telomere lengths (delta tel, the difference between the observed telomere length and the length expected from the line of best fit drawn in panel a) for healthy control subjects (open circles, n = 112), NHP2 family members (as in A), and patients with dyskerin mutations (dashes, n = 67). (C) TERC levels, expressed as a TERC/ABL ratio, in healthy control individuals (open circles, n = 24), NHP2 family members (as in A), and patients with dyskerin mutations (dashes, n = 27). ...
The mechanism of telomere elongation by telomerase. In this example the telomerase enzyme is synthesizing the repeated sequence TTGGGG, which is the telomeric sequence of Tetrahymena thermophila.. The first detection of telomerase activity, in the ciliateTetrahymena thermophila, was followed by its detection in a variety of organisms including vertebrates, yeast, and plants. In the absence of telomerase activity, telomeres shorten with each cell division. Normal human somatic cells lack detectable telomerase activity, whereas telomerase is activated in germ cells, immortalized cells and the majority of primary tumors. The correlation between telomerase activity and tumor growth has spurred investigations of the possiblities to use telomerase activity as a target for anticancer drug treatments.. Our identification of much longer telomeric repeat units (16-26 bp) in several yeast species has expanded the previous range of telomeric repeat sequences to include not only more complex sequences, but ...
Mutations in the gene for telomerase reverse transcriptase (hTERT) are associated with diseases including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis and cancer. Understanding the molecular basis of these telomerase-associated diseases requires dependable quantitative measurements of telomerase enzyme activity. Furthermore, recent findings that the human POT1-TPP1 chromosome end-binding protein complex stimulates telomerase activity and processivity provide incentive for testing variant telomerases in the presence of these factors. In the present work, we compare multiple disease-associated hTERT variants reconstituted with the RNA subunit hTR in two systems (rabbit reticulocyte lysates and human cell lines) with respect to telomerase enzymatic activity, processivity and activation by telomere proteins. Surprisingly, many of the previously reported disease-associated hTERTalleles give near-normal telomerase enzyme activity. It is possible that a small deficit in telomerase activity is
In the new paper published in Nature Communications, the group of Gian Paolo Dotto describes the central role of CSL in telomere homeostasis of dermal fibroblasts with important implications for genomic instability of cancer stromal cells
See related article, pp 420-425. The discovery that critical telomere shortening initiates replicative senescence triggered a vast body of epidemiological studies exploring its implications for human aging. These studies demonstrated that telomeres-typically measured in the DNA isolated from blood cells-clearly shorten with age. On average, shorter telomeres were found in subjects with atherosclerosis and independently predicted atherosclerotic cardiovascular disease (ACVD)-associated mortality. Moreover, Mendelian randomization studies point to a causal role for shorter telomere length in ACVD, lending support to the hypothesis that the protective antitumor mechanism elicited by critical telomere attrition may act at the expense of unsuccessful cardiovascular aging.1 Yet, consensus is lacking on the mechanism underlying the presumed associations between shorter telomeres, atherosclerosis, and ACVD. This problem was addressed in the epidemiological research by Toupance et al,2 published in the ...
Telomerase, a ribonucleoprotein with reverse transcriptase activity, enables human cells to maintain chromosomal stability and to proliferate without limits. Various stud..
Telomerase activity is involved in telomere length maintenance. Leukocytes, unlike many human somatic tissues, have detectable telomerase activity. These cells provide a normal human cell type in which to study telomerase. We studied the regulation of telomerase activity and the telomerase RNA component as leukocytes were stimulated to enter the cell cycle. In primary human leukocytes stimulated with phytohemagglutinin, telomerase activity increased , 10-fold as naturally quiescent cells entered the cell cycle. Antibodies to the T cell receptor (TCR)/CD3 complex and the costimulatory CD28 receptor induced telomerase activity in a T cell-enriched population of cells. Rapamycin, an immunosuppressant that blocks TCR/CD3 signal transduction pathways and cdk2 activation, blocked telomerase induction. Hydroxyurea, an inhibitor of S phase, did not block cdk2 kinase activity or telomerase activation. In summary, telomerase is regulated in G1 phase as normal human T cells enter the cell cycle.. ...
We sought to examine the relationship between elevated transferrin saturation (TS) and measures of health status (telomere length and patient-reported health-related quality of life) to assess whether elevated TS is associated with negative patient outcomes beyond increased risk for morbidity and mortality, using a cross-sectional analysis of the Hemochromatosis and Iron Overload Screening Study supplemented with assays for leukocyte telomere length in adults ≥25 years old (n = 669). Among individuals with elevated TS (≥45 % for women and ≥50 % for men), who also had a usual source of care, only 5.2 % reported ever being told by a doctor that they had an elevated iron condition. In a fully adjusted general linear regression model controlling for demographic characteristics as well as health conditions associated with iron overload, elevated TS versus non-elevated TS was associated with worse general health status (60.4 vs. 63.8, P , 0.05), mental health status (76.5 vs. 82.2, P , 0.0001) ...
To find an answer, the team started a long-tem study on changes in telomere length. In the Vienna Woods in Austria they regularly checked 130 nest-boxes that are occupied by free-living dormice. The researchers collected the rodents buccal mucosa for three years. Thus, they could extract the DNA and determine the relative telomere length for each dormouse individually using qPCR. With this method scientists can define the amount of target DNA compared to a reference gene of the same sample.. Elongation does not only occur, it even increases in older edible dormice. We found out that the telomeres were shortened in young animals but length significantly increased once the dormice were six years old or older. To top it all, the rate of telomere elongation also increased with increasing age of the dormice, says Franz Hoelzl.. Among the variables tested, only age significantly affected RTL in a non-linear pattern with telomere length decreasing in younger and increasing in older dormice. Hoelz ...
Recent work has yielded considerable information concerning the structure and function of telomeres and their associated sequences in the budding yeast Saccharomyces cerevisiae. The structure and maintenance of telomeres depends not only on the RNA template and the catalytic subunit of telomerase, b …
Objective: Studies in white people have shown that telomere length, a marker of biological ageing, is shorter in individuals with coronary artery disease (CAD). South Asian Indians have a high prevalence of CAD, especially premature CAD. We examined the association of telomere length with CAD in Indian subjects.. Design: Case-control study.. Setting: Mumbai, India.. Subjects: 238 consecutive patients (aged 29-82 years), admitted to Cumballa Hill Hospital for coronary investigations or treatment and 238 control subjects (aged 30-87 years) from the same area without any clinical evidence of CAD.. Methods: Mean leucocyte telomere length was measured using a polymerase chain reaction (PCR)-based assay and expressed as a ratio (T/S ratio) of the telomere signal to that of a control single copy gene.. Results: T/S ratio was significantly lower in CAD cases compared with controls (cases 1.21 (95% CI 1.16 to 1.26); controls 1.33 (1.28 to 1.38); p = 0.0003), equivalent to approximately 166 base pairs. ...
Fusion of critically short or damaged telomeres is associated with the genomic rearrangements that support malignant transformation. We have demonstrated the fundamental contribution of DNA ligase 4-dependent classical non-homologous end-joining to long-range inter-chromosomal telomere fusions. In contrast, localized genomic recombinations initiated by sister chromatid fusion are predominantly mediated by alternative non-homologous end-joining activity that may employ either DNA ligase 3 or DNA ligase 1. In this study, we sought to discriminate the relative involvement of these ligases in sister chromatid telomere fusion through a precise genetic dissociation of functional activity. We have resolved an essential and non-redundant role for DNA ligase 1 in the fusion of sister chromatids bearing targeted double strand DNA breaks that is entirely uncoupled from its requisite engagement in DNA replication. Importantly, this fusogenic repair occurs in cells fully proficient for non-homologous ...
The foundational understanding of the role of telomeres and telomerase in disease has been rooted in curiosity-driven science, in simple systems and model organisms (22). One major theme that emerges at the intersection between this fundamental science and disease genetics is that relatively small, subtle changes affecting telomerase abundance or function can influence telomere length and, in turn, disease risk (23). The exquisite sensitivity of telomere length to these small changes is related to the fact that telomerase is in very low abundance and its activity is tightly regulated. In yeast, mice, and humans, the number of telomere ends exceeds the number of telomerase molecules (refs. 24, 25, and reviewed in refs. 23, 26). The low levels of telomerase set up a system wherein not all telomeres are elongated during a given cell cycle even when telomerase is normally expressed (27). There are at least three additional limits on telomerase activity. The first is that the essential telomerase ...
Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by the presence of short telomeres at presentation. Mutations in ten different genes, whose products are involved in the telomere maintenance pathway, have been shown to cause DC. The X-linked form is the most common form of the disease and is caused by mutations in the gene DKC1, encoding the protein dyskerin. Dyskerin is required for the assembly and stability of telomerase and is also involved in ribosomal...
Telomeres, specialized structures found at the end of chromosomes, are involved in the replication and stability of the chromosome. Telomeres consist of tandem repeats of the DNA sequence TTAGGG and associated proteins. During the process of cell division, most human cells undergo telomere shortening because they lose some of these tandem repeats, approximately 50 to 200 base pairs (bp) per cell division (1, 2). When telomeres become critically short, cells either become senescent or undergo apoptosis.. The enzyme telomerase plays an important role in the formation, maintenance, and renovation of telomeres. Telomerase, or telomere terminal transferase, is a ribonucleoprotein that catalyzes the de novo synthesis and elongation of telomeric repeats at chromosomal ends by using an RNA segment within the RNA subunit as a template (3-5). Telomerase consists of at least two essential components, the RNA template (hTERC) and the catalytic subunit (hTERT).. Cancer development is accompanied by the ...
Exposure to benzene, a known leukemogen and probable lymphomagen, has been demonstrated to result in oxidative stress, which has previously been associated with altered telomere length (TL). TL specifically has been associated with several health outcomes in epidemiologic studies, including cancer risk, and has been demonstrated to be altered following ... read more exposure to a variety of chemical agents. To evaluate the association between benzene exposure and TL, we measured TL by monochrome multiplex quantitative PCR in 43 workers exposed to high levels of benzene and 43 age and sex-matched unexposed workers in Shanghai, China. Benzene exposure levels were monitored using organic vapor passive dosimetry badges before phlebotomy. The median benzene exposure level in exposed workers was 31 ppm. The mean TL in controls, workers exposed to levels of benzene below the median (≤31 ppm), and above the median (,31 ppm) was 1.26±0.17, 1.25±0.16, and 1.37±0.23, respectively. Mean TL was ...
Telomerase is a reverse transcriptase that adds telomeric repeats (TTAGGG)n to chromosomal ends, compensating for the telomere shortening that occurs with DNA replication. In normal human somatic cells, telomerase is repressed and telomeres progressively shorten, leading to limited lifespan and senescence. Reactivation of telomerase activity is associated with human cancer and cell immortalization. Approximately 85% of human cancers, including breast, prostate, stomach, bladder, colon, and liver cancer, have telomerase activity, whereas most normal somatic cells do not. The specificity of telomerase to human cancer has led to investigations of telomerase activity and expression as a tumor marker. For example, the presence of telomerase activity in human urine has been identified as a marker for human bladder carcinoma. Human telomerase consists of three major subunits: a catalytic protein subunit called hTERT (for human TElomerase Reverse Transcriptase), a template RNA called hTR, and telomerase
Previous work from the de Lange lab showed that TRF2, a shelterin protein that binds to the duplex part of the telomere, is crucial for telomere protection. Without TRF2, telomeres activate a DNA damage signal and are repaired by the same pathways that act on DNA breaks. TRF2 brings a second shelterin protein, POT1, to the telomeres. Because POT1 binds to single-stranded telomeric DNA present at the very end of the chromosomes, the de Lange lab asked how POT1 contributes to the protection of telomeres.. We had previously removed TRF2 from mouse cells and seen many dramatic phenotypes, says de Lange, all of the telomeres ligate together; there is a massive DNA damage response and the cells basically die. We argued that if the function of TRF2 was to bring POT1 to the DNA, then we should observe the same phenotype if we removed POT1.. To determine if this was the case, graduate student Dirk Hockemeyer, the first author of the paper, decided to remove the POT1 gene from mice. Humans have one ...
Dowd, Jennifer Beam; Bosch, Jos A.; Steptoe, Andrew; Jayabalasingham, Bamini; Lin, Jue; Yolken, Robert H.; & Aiello, Allison E. (2017). Persistent Herpesvirus Infections and Telomere Attrition over 3 Years in the Whitehall II Cohort. Journal of Infectious Diseases, 216(5), 565-72.
Let me tell you something I read recently about telomeres. After 2009 Nobel Prize went to Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase, there are lots of articles about telomeres on the web. Alexey Olovnikov discovered telomeres in 1973. He found that the tiny units of DNA (telomeres) at the end of each chromosome shorten in time because they cant replicate completely every time the cell divides. So, as you get older, your telomeres get shorter and shorter. Eventually, DNA replication and cell division stops completely, at which point you die. But, some researches are showing that certain nutrients play a significant role in protecting telomere length. That means that we can influence telomeres length. Vitamins B9 and B12 can influent telomere length, as well as vitamin D3, zinc, omega-3 fatty acids, iron, and vitamins C and E. Telomere shortening has been linked to the type 2 diabetes, ...
TY - JOUR. T1 - The Saccharomyces telomere-binding protein Cdc13p interacts with both the catalytic subunit of DNA polymerase α and the telomerase-associated Est1 protein. AU - Qi, Haiyan. AU - Zakian, Virginia A.. PY - 2000/7/15. Y1 - 2000/7/15. N2 - Saccharomyces telomeres consist of -350 bp of C1-3A/TG1-3 DNA. Most of this -350 bp is replicated by standard, semiconservative DNA replication. After conventional replication, the C1-3A strand is degraded to generate a long single strand TG1-3 tail that can serve as a substrate for telomerase. Cdc13p is a single strand TG1-3 DNA-binding protein that localizes to telomeres in vivo. Genetic data suggest that the Cdc13p has multiple roles in telomere replication. We used two hybrid analysis to demonstrate that Cdc13p interacted with both the catalytic subunit of DNA polymerase α, Pol1p, and the telomerase RNA-associated protein, Est1p. The association of these proteins was confirmed by biochemical analysis using full-length or nearly full-length ...
Telomeres When telomeres of chromosomes shorten with continued cell divisions, the chromosome ends may also fuse, forming ... Chromosomal inversion Telomeres Cytogenetics Nuclear radiation Intellectual disorders Nussbaum, Robert; McInnes, Roderick; ... Boukamp, Petra; Popp, Susanne; Krunic, Damir (2005-11-01). "Telomere-Dependent Chromosomal Instability". Journal of ...
Telomere is a mysterious terrorist organization that is behind the attacks on The Bund. Fake Mina A female vampire who posed as ... It is later revealed that he is a mole for Telomere. The Eight Elite consists of the best hunters in the Earth Clan. Each ... Hysterica had a habit of referring to her slaves as "Pigs." In the anime, she worked for Telomere, but still tried to contact ... In the anime, it is heavily suggested one or all of them are controlling Telomere, a terrorist group created to kill Mina. Also ...
Thus, reprogramming leads to the restoration of embryonic telomere length, and hence increases the potential number of cell ... It was found that reprogramming leads to telomere lengthening and subsequent shortening after their differentiation back into ... West, M. D.; Vaziri, H (2010). "Back to immortality: The restoration of embryonic telomere length during induced pluripotency ... Marión, R. M.; Blasco, M. A. (2010). "Telomere rejuvenation during nuclear reprogramming". Current Opinion in Genetics & ...
Author of The Telomere (1995). Professor Thomas Burton Loram Kirkwood CBE (1951-) Dr James Brown (1975-)Elected to membership ( ...
A dosage of 800 mg/day danazol was found to increase telomere length in patients with telomere diseases in a phase I/II ... "Danazol Treatment for Telomere Diseases". N.E.J.M. 374 (20): 1922-31. May 2016. doi:10.1056/NEJMoa1515319. Hoffman, Barbara L; ... The study was halted early, after telomere attrition was reduced in all 12 patients who could be evaluated. 12 of 27 patients ... The primary efficacy endpoint was a 20% reduction in the annual rate of telomere attrition measured. Toxic effects formed the ...
When that chromosome subsequently replicates it forms two sister chromatids which both lack a telomere. Since telomeres appear ... Since the two resulting chromatids lack telomeres, when they replicate the BFB cycle will repeat, and will continue every ... The BFB cycle begins when the end region of a chromosome, called its telomere, breaks off. ... Murnane, John P. (2012). "Telomere dysfunction and chromosome instability". Mutation Research. 730 (1-2): 28-36. doi:10.1016/j. ...
Jef Akst (2015). "Another Telomere-Regulating Enzyme Found". The Scientist (November 12). Kastan MB, Lim DS (2001). "The many ... and telomere maintenance. Therefore, a defect in ATM has severe consequences in repairing certain types of damage to DNA, and ... http://www.hprd.org/protein/06347 Drosophila telomere fusion - The Interactive Fly GeneReviews/NCBI/NIH/UW entry on Ataxia ...
In plants, the telomere sequence is conserved which implies this strategy can be utilized to successfully construction ... Yu, W.; Lamb, J. C.; Han, F.; Birchler, J. A. (2006). "Telomere-mediated chromosomal truncation in maize". Proceedings of the ... The minimum constituent parts of a chromosome (centromere, telomere and DNA replication sequences) are assembled This is done ... A minichromosome is a small chromatin-like structure consisting of centromeres, telomeres and replication origins and little ...
Telomeres form the terminal region of mammalian chromosomes and are essential for stability and aging and play central roles in ... Telomeres have been long considered transcriptionally inert DNA-protein complexes until it was recently shown that telomeric ... Although early, these studies suggest an involvement for telomeric ncRNAs in various aspects of telomere biology. In mouse ... These ncRNAs are heterogeneous in length, transcribed from several sub-telomeric loci and physically localise to telomeres. ...
Each time a cell in the body divides, its telomeres become shorter. Eventually, telomeres shorten to the point where the cell ... In humans, aging is strongly correlated with the length of an individual's telomeres, the repetitive DNA at the ends of each ... Are Telomeres the Key to Aging and Cancer?, The University of Utah, Genetic Science Learning Center, archived from the original ... Telomere Telomerase Shea, Steven. "History of Isagenix". Complete Life Wellness. Retrieved 19 July 2015. Geron Corp. Licensee ...
In recent years Blackburn and her colleagues have been investigating the effect of stress on telomerase and telomeres with ... Blackburn co-discovered telomerase, the enzyme that replenishes the telomere. For this work, she was awarded the 2009 Nobel ... Previously she was a biological researcher at the University of California, San Francisco, who studied the telomere, a ... Intimate partner violence was found to shorten telomere length in formerly abused women versus never abused women, possibly ...
The shrinking of telomeres occurs in somatic cells where telomerase, the enzyme in control of telomere lengthening, is not ... Another component of aging is the gradual shortening of telomeres located at the end of chromosomes. Telomeres are repetitive ... This increase in non-coding RNA transcription aided telomere stability, making the exercise group's telomeres less likely to be ... However, it has been seen that telomeres can transcribe non-coding RNA, or functional RNAs that do not get translated into ...
Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme ... Telomerase are found specifically to target shorter telomere over longer telomere, due to various regulatory mechanisms inside ... Although cells with long telomeres did not experience apoptosis, they developed mortal characteristics and underwent telomere ... It elongates the telomeres of stem cells, which, as a consequence, increases the lifespan of the stem cells by allowing for ...
Ty5 is used as a model system by which to understand the biology of the telomere and heterochromatin. The Ty5 retrotransposon ... Pryde FE, Louis EJ (November 1997). "Saccharomyces cerevisiae telomeres. A review". Biochemistry Mosc. 62 (11): 1232-41. PMID ... which interact with specific cis DNA sequences at the telomeres, rDNA and HM loci. These proteins, including Rap1p and the ... "The Saccharomyces Ty5 retrotransposon family is associated with origins of DNA replication at the telomeres and the silent ...
S. pombe has a shelterin-like telomere complex while S. cerevisiae does not. S. cerevisiae is in the G1 phase of the cell cycle ... Price CM, Boltz KA, Chaiken MF, Stewart JA, Beilstein MA, Shippen DE (2010). "Evolution of CST function in telomere maintenance ... telomere function, gene splicing, and many other cellular processes. S. pombe's genome was fully sequenced in 2002, the sixth ...
1992). "Telomere length predicts replicative capacity of human fibroblasts". Proc. Natl. Acad. Sci. U.S.A. 89: 10114-10118. ... 1990). "Telomere reduction in human colorectal carcinoma and with ageing". Nature. 346: 866-868. doi:10.1038/346866a0. PMID ... 1996). "Accelerated telomere shortening in ataxia telangiectasia". Nat. Genet. 13: 350-353. doi:10.1038/ng0796-350. Hastie ND, ... Frenck RW Jr, Blackburn EH, Shannon KM (1998). "The rate of telomere sequence loss in human leukocytes varies with age". Proc. ...
Telomere. He is the protagonist of the story and a member of the Junior Leaguers. Not having powers, he focuses more on ... Telomere- Creator of Lil` Heroes Handbook. He can live for a very long time (currently 273 years old). He doesn't consider ... When the citizens of Superopolis begin rejecting Telomere's crispy potato chips for the bland-flavored Pseudo chips, the potato ...
Zhang H, Cohen SN (Dec 2004). "Smurf2 up-regulation activates telomere-dependent senescence". Genes & Development. 18 (24): ...
T-loops and G-quadruplexes are described as the two tertiary DNA structures that protect telomere ends and regulate telomere ... CST protection of telomeres for mammals occurs under conditions of replication stress. But when not replicating DNA, mammals ... Lue NF, Zhou R, Chico L, Mao N, Steinberg-Neifach O, Ha T (2013). "The telomere capping complex CST has an unusual ... In fungus, the CST complex has been shown to unfold higher order G-tailed structures, such as occur with telomere exposure ...
One hypothesis for the detrimental results of aging is associated with the loss of telomeres, the end segments of chromosomes ... Telomere loss has also been associated with decreased mitochondrial function. Deficiency of telomerase reverse transcriptase ( ... Therefore, the loss of telomeres and TERT that comes with aging has been associated with impaired mitochondrial biogenesis. ... Sahin, Ergün; DePinho, Ronald A. (2012-05-16). "Axis of ageing: telomeres, p53 and mitochondria". Nature Reviews. Molecular ...
van Overbeek M, de Lange T (2006). "Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S ... SNM1B/Apollo protein appears to be a crucial factor in telomere maintenance, independent of its function in repairing DNA inter ... Using an SNM1B/Apollo knockout mouse model, evidence was obtained that SNM1B/Apollo protein is required to protect telomeres ... Freibaum BD, Counter CM (2006). "hSnm1B is a novel telomere-associated protein". J. Biol. Chem. 281 (22): 15033-6. doi:10.1074/ ...
TRF1 along with TRF2 normally prevents telomerase from adding more telomere units to telomeres. But when telomere lengthening ... TRF2 (Telomere Repeat Factor 2) TRF2 is a homodimeric protein that binds to the double-stranded TTAGGG region of the telomere ... When telomeres are to be lengthened, TPP1 is a central factor in recruiting telomerase to telomeres. The gene which encodes for ... TRF1 (Telomere Repeat Factor 1): TRF1 is a homodimeric protein that binds to the double-stranded TTAGGG region of the telomere ...
Interestingly, telomere lengthening in cancer cells by the alternative lengthening of telomeres (ALT) mechanism has also been ... Telomeres maintain the integrity of the ends of linear chromosomes during replication and protect them from being recognized as ... MRN participates in telomere maintenance primarily via association with the TERF2 protein of the shelterin complex. Additional ... Additionally, knockdown of MRN has been shown to significantly reduce the length of the G-overhang at human telomere ends, ...
... that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate ... Protection of telomeres protein 1 is a protein that in humans is encoded by the POT1 gene. This gene is a member of the ... "Entrez Gene: POT1 POT1 protection of telomeres 1 homolog (S. pombe)". Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, ... Loayza D, De Lange T (Jun 2003). "POT1 as a terminal transducer of TRF1 telomere length control". Nature. 423 (6943): 1013-8. ...
A telomere is a region of repetitive sequences at each end of eukaryotic chromosomes in most eukaryotes. Telomeres protect the ... Telomerase reverses telomere shortening. Telomerase replaces short bits of DNA known as telomeres, which are otherwise ... Cherif H, Tarry JL, Ozanne SE, Hales CN (2003). "Ageing and telomeres: a study into organ- and gender-specific telomere ... A comparative biology study of mammalian telomeres indicated that telomere length of some mammalian species correlates ...
The counting device for cell doublings is the telomere, which decreases in size (loses nucleotides at the ends of chromosomes) ... About 85% of cancers upregulate telomerase to extend their telomeres and the remaining 15% use a method called the Alternative ... Cancer cells bypass this barrier by manipulating enzymes that increase the length of telomeres. Thus, they can divide ... Greenberg, RA (March 2005). "Telomeres, crisis and cancer". Current molecular medicine. 5 (2): 213-8. doi:10.2174/ ...
Telomere-associated DNA damage also increases in timeless depleted cells, along with the delay of telomere replication. Swi1 is ... 2012). "Timeless Preserves Telomere Length by Promoting Efficient DNA Replication through Human Telomeres". Cell Cycle. 11 (12 ... Downregulation of the timeless gene in human carcinoma cells leads to shortened telomeres, indicating its role in telomere ... This association between timeless and telomeres is indicative of the gene's possible association with cancer. A single ...
The lab's future work will focus more on identifying the processing and regulation of telomeres and telomere elongation. ... Greider chose to use RNA degrading enzymes and saw that the telomeres stopped extending, which was an indication that RNA was ... Hopkins "Telomere" expert Carol Greider shares Germany's largest science prize "Former Davis resident receives Nobel Prize". ... Greider pioneered research on the structure of telomeres, the ends of the chromosomes. She was awarded the 2009 Nobel Prize for ...
Banks, D. A. (1997). "Telomeres, Cancer, and Aging. Altering the Human Life Span". JAMA: The Journal of the American Medical ... Haussmann MF, Winkler DW, O'Reilly KM, Huntington CE, Nisbet IC, Vleck CM (2003). "Telomeres shorten more slowly in long-lived ... life span and number of double bonds Selected species of birds and mammals show an inverse relationship between telomere rate ...
Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, Cawthon RM (December 2004). "Accelerated telomere shortening in ...
... Lustig, Arthur J. alustig at MAILHOST.TCS.TULANE.EDU Wed Sep 25 10:36:35 EST 1996 *Previous ... the role of the telomere-binding protein RAP1 in telomere size control and telomeric silencing (see Lustig et al. MCB 16: 2483- ... that appears to combine elements of intrachromatid recombination and pairing of non-homologous telomeres to regulate telomere ... POSTDOCTORAL POSITIONS AVAILABLE TO STUDY TELOMERE SIZE REGULATION AND TELOMERIC SILENCING IN SACCHAROMYCES CEREVISIAE. I am ...
Telomere length predicts replicative capacity of human fibroblasts. R C Allsopp, H Vaziri, C Patterson, S Goldstein, E V ... Telomere length predicts replicative capacity of human fibroblasts. R C Allsopp, H Vaziri, C Patterson, S Goldstein, E V ... Telomere length predicts replicative capacity of human fibroblasts. R C Allsopp, H Vaziri, C Patterson, S Goldstein, E V ... indicating that cell strains with shorter telomeres underwent significantly fewer doublings than those with longer telomeres. ...
This is known as the telomere replication problem. In this article, different and new aspects of telomere replication, that can ... Telomere replication is a major challenge because many obstacles to the progression of the replication fork are concentrated at ... In particular, we will focus on the functions of shelterin and the replisome for the preservation of telomere integrity ... Telomeres are complex nucleoprotein structures that protect the extremities of linear chromosomes. ...
Their behavior suggested that they carried functional telomeres. Here we show that efficient healing by de novo telomere ... Healing of Euchromatic Chromosome Breaks by Efficient de novo Telomere Addition in Drosophila melanogaster. Simon W. A. Titen ... Healing of Euchromatic Chromosome Breaks by Efficient de novo Telomere Addition in Drosophila melanogaster. Simon W. A. Titen ... Healing of Euchromatic Chromosome Breaks by Efficient de novo Telomere Addition in Drosophila melanogaster. Simon W. A. Titen ...
Two groups conclude that factors near telomeres alter the telomeres nuclear positioning and thus their length. ... The lengths of telomeres, which are caps for chromosome ends, are kept consistent by a pathway that "counts" the number of Rap1 ... Cells need a critical amount of it, but if they get too much then telomeres might get added anywhere a double-stranded DNA ... Her team shows that the anchoring of individual telomeres near the NE is variable and correlates with the composition of the ...
Telomere length shortens with age in all replicating somatic cells. It has been shown that tobacco smoking enhances telomere ... Telomere shortening in smokers with and without COPD. M. Morlá, X. Busquets, J. Pons, J. Sauleda, W. MacNee, A. G. N. Agustí ... Telomere shortening in smokers with and without COPD Message Subject (Your Name) has sent you a message from European ... Telomere length was determined by fluorescence in situ hybridisation in circulating lymphocytes harvested from 26 never-smokers ...
While TERT maintains telomere length under standard conditions, telomeres under increased stress shorten as fast as in cells ... We also know that progressive telomere shortening is tied to aging and age-related disease, and a number of different groups ... There is also evidence for a telomere-independent survival function of telomerase. However, its mechanism is not understood. We ... More On Telomere Shortening and Mitochondrial Dysfunction. Permalink , No Comments Yet , Add a Comment , Share , Posted by ...
This review discusses the role of telomeres and telomerase in OA and OP pathologies and focuses on the usability of telomere ... Telomere length and telomerase activity in osteoporosis and osteoarthritis (Review). *Authors: *Persefoni Fragkiadaki ... A number of studies have demonstrated that telomere shortening may contribute to OA and OP as an epigenetic factor. Therefore, ... OA and OP have been characterized as age‑related diseases and have been associated with telomere shortening and altered ...
Leukocyte telomere length, representing the mean length of all telomeres in leukocytes, is ostensibly a bioindicator of human ... and it grew stronger with increasing intrapair difference in all telomere parameters. Leukocyte telomere dynamics might help ... Telomere length and mortality: a study of leukocytes in elderly Danish twins Kimura, M., Hjelmborg, J. v.B., Gardner, J., ... The proportions derived from the intrapair comparisons indicated that the shorter telomeres predicted the death of the first co ...
Telomere resolvase is an enzyme found in bacteria which contain linear plasmids. Linear plasmid contain hair pin turns at the ... Telomere resolvase then cuts the structure and reforms the hair pin turns forming two linear plasmids.. ...
A telomere is a region of repetitive nucleotide sequences at each end of a chromosome. Telomere may also refer to: Telomere ( ... insect morphology), a type of genital clasper Telomere resolvase, an enzyme found in bacteria which contain linear plasmids. ...
... and terminal restriction fragment analysis have traditionally been regarded as the gold standard for measuring telomere length ... New study may offer a breakthrough in treating telomere diseases. *Crick study reveals vital protective role of telomere t- ... Approaches and challenges in studies of telomere length. When a research study wants to include telomere length in the analysis ... The length of the shortest telomere represents a much better indicator of cellular aging than the average telomere length, ...
Telomeres become shorter every time a cell divides. Once they are too short, telomeres send a signal for the cell to stop ... New Insight into Telomere Regulation New Insight into Telomere Regulation * Prenatal Lead Exposure Linked with Decreased ... oxoG lesion arises in telomeres dictates whether telomerase is inhibited or stimulated and thus determines whether the telomere ... Research, funded in part by NIEHS, has uncovered new details about the regulation of telomeres. These repeated DNA sequences ...
... and protection of telomeres 1 (POT1) - which are essential for telomere protection and for regulating telomere elongation. The ... a , Simplified schema of the haematopoiesis hierarchy with intact telomere length (left panel) and in the presence of telomere ... The telomere syndromes.. Armanios M1, Blackburn EH.. Author information. 1. Department of Oncology, Sidney Kimmel Comprehensive ... At every age, telomere length displays a normal distribution that is defined by the percentile lines labelled on the right. ...
Telomere News and Research. RSS A telomere is a region of repetitive DNA at the end of a chromosome, which protects the end of ... Telomere shortening in adulthood is not caused by smoking, say researchers A new study suggests that telomere length in adults ... Study: Smoking does not shorten the length of telomeres A new study has surprised the medical world, finding that smoking does ... People born with short telomeres found to have short-lived immune system cells Scientists at Johns Hopkins say they have found ...
The telomere is a nucleoprotein structure comprising the terminal section of a eukaryotic chromosome. It has a specialized ...
... known as telomeres, protect chromosome ends from nucleolytic degradation and DNA repair activities. Conventional DNA ... Telomere Length Short Telomere Cajal Body Telomere Elongation Nonextendible State These keywords were added by machine and not ... Correct telomere length setting is crucial for long-term survival. The telomere length reserve must be sufficient to avoid ... In vivo analysis of telomere elongation kinetics shows that telomerase does not act on every telomere in each cell cycle but ...
... although telomere shortening may play a role in limiting cellular life span, there is no evidence that telomere shortening ... long-lived species often have shorter telomeres than do short-lived species, indicating that telomere length probably does not ... 56Kakuo S, Asaoka K, Ide T. Human is a unique species among primates in terms of telomere length. Biochem Biophys Res Commun. ... Telomeres shorten during ageing of human fibroblasts. Nature 1990;345:458-460. 54Vaziri H, Dragowska W, Allsopp RC, Thomas TE, ...
The question remains whether Dollys short telomeres were an exception or a general fact, which would differ from the telomeres ... inherited shortened telomeres from her cell donor and that her telomeres were further shortened by the brief culture of donor ... This observation was challenged by a recent report9 that showed calves cloned from fetal cells have longer telomeres than their ... The question remains whether Dollys short telomeres were an exception or a general fact, which would differ from the telomeres ...
... rapid advances in technology have equipped us with a variety of tools and platforms to ask fundamental questions of telomere ... Cancer progression Cell growth Chromatin Genomics Model systems Protein interaction networks Proteomics Telomere DNA Telomere ... Telomeres and Telomerase: Methods and Protocols, Second Edition builds upon the telomerase assays featured in the popular first ... Authoritative and practical, Telomeres and Telomerase: Methods and Protocols, Second Edition serves as an ideal, up-to-date ...
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... and telomere length implies that stress preceded telomere shortening, because telomere length cannot have influenced the number ... A) Average telomere length and SE are shown. The high-stress group had shorter telomeres even after controlling for age and BMI ... Therefore, in translating telomere shortening to years of aging, we based our estimates on studies averaging telomere ... Telomeres are DNA-protein complexes that cap chromosomal ends, promoting chromosomal stability. When cells divide, the telomere ...
In human, the mode of telomere length inheritance appears to be paternal and telomere length differs between sexes, with ... To test the influence of sex chromosomes on telomere length, we investigated inheritance and sex-specificity of telomere length ... Inheritance of telomere length in a bird.. Horn T1, Robertson BC, Will M, Eason DK, Elliott GP, Gemmell NJ. ... with many correlations reported between telomere length and age-related diseases, cancer and death. While telomere length is ...
... those whose donor white blood cells had longer telomeres had higher survival rates five-years after transplant ... Donor telomere length and survival after hematopoietic cell transplantation in patients with severe aplastic anemia. * ... Telomere length has been implicated in the development of several cancers, as well as other health conditions. This study was ... Telomeres are complex structures on the ends of chromosomes that help maintain chromosome integrity. They shorten naturally as ...
... collectively called a telomere. With each cell division, telomeres are copied and reassembled through a process called telomere ... I will use purified proteins to study telomere replication in a test tube. This novel approach will allow me to use biochemical ... My work will provide fundamental molecular insights into the biology of telomeres, which will help us better understand human ... Understanding the mechanism of telomere replication. Sir Henry Dale Fellowships Year of award: 2019 ...
There is a correlation between diabetes and telomere shortening; however, very little is known about telomere homeostasis in ... There is a correlation between diabetes and telomere shortening; however, very little is known about telomere homeostasis in ... Telomere homeostasis in placentas from pregnancies with uncontrolled diabetes. *Biron-Shental T ... TERC gene copy number and telomere capture were evaluated by FISH. Results Telomerase expression was significantly lower in the ...
Cells age if the telomeres are shortened, but when "telomerase activity is high, telomere length is maintained, and cellular ... Americans Win Nobel for Telomere Discovery. - Three American scientists, whose research held the key to unlocking chromosome ... Blackburn and Szostak discovered that the solution to chromosome replication was contained in telomeres, the structure at the ... Greider was a graduate student when she and and Blackburn identified telomerase, the enzyme that makes telomere DNA. ...
Telomere Dynamics Telomere overhang generation processes and the end-replication problem. Telomeres are composed of TTAGGG ... From previous studies, we found that telomere overhang generation processes may be important in determining telomere shortening ... We found that the telomere lagging strand has an overhang of ~110 nt and the leading strand has an overhang of ~30 nt. These ... If that were correct, the rate of telomere shortening would only be around 8-10 bp per cell division (RNA primer size ÷ 2 = (16 ...
Find telomere Stock Images in HD and millions of other royalty-free stock photos, illustrations, and vectors in the ... Telomere stock photos. 568 Telomere stock photos, vectors, and illustrations are available royalty-free. See telomere stock ... Telomeres DNA and telomere length medical concept on the end caps of a chromosome as a symbol for aging and genetic protection ... Telomeres length loss with DNA and shortening telomere medical concept as a tree with falling leaves on the end caps of a ...
telomeres Archive antiaging100 years ago the world absolute poverty rate was as bad as the poorest country today. No Comments ...
Postdoctoral position to study telomere structure and function. A postdoctoral position is available to investigate telomere ... telomeres at Tulane. Lustig, Arthur J. alustig at MAILHOST.TCS.TULANE.EDU Mon Mar 10 09:14:06 EST 1997 *Previous message: THE ... We have had a long-standing fascination in telomere structure and function and are currently focusing on two broad areas: 1) ... The mechanisms of nucleation and inheritance of telomeric silencing (e.g. MCB 16: 2843); and 2) the mechanism of telomere size ...
Observable: telomere length. Description. The average length of telomeres.. Qualifiers. decreased, increased, normal, abnormal ...
Telomere and Telomerase. The safety and scientific validity of this study is the responsibility of the study sponsor and ...
Telomere homeostasis is tightly linked to cellular metabolism, and in particular with mitochondrial physiology, which is also ... Magnesium plays an important role in many of the processes involved in regulating telomere structure, integrity and function. ... This review explores the mechanisms that maintain telomere structure and function, their influence on circadian rhythms and ... The pervasive role of magnesium in telomere homeostasis is also highlighted. ...
This process shortens the telomeres or scalar antenna on the DNA which as they get shorter limits the ability to grow new cells ... We use the Viopulsar for activating the amazing Telomerase enzyme and the Telomeres. Facial: 2-3 sessions weekly Set the SWL on ... scientists have recently discovered an enzyme called the Telomerase enzyme which increases the length of the telomere thereby ... and the violet laser spectrum optimizes and enhances this quantum rejuvenation effect of activating Telomerase and the Telomere ...
Schematic overview depicting either (A) shorter inherited telomere length (TL), or (B) accelerated telomere attrition (ΔTL), as ... telomeres versus (2) higher telomere attrition rates (Figure). The study provides evidence supporting the first hypothesis. In ... Telomeres and Atherosclerosis. The Intricate Pursuit of Mechanistic Insight Through Epidemiology. Tim De Meyer, Marc L. De ... These studies demonstrated that telomeres-typically measured in the DNA isolated from blood cells-clearly shorten with age. On ...
It has long been presumed impossible to measure telomeres in vertebrate DNA by PCR amplification with oligonucleotide primers ... Telomere measurement by quantitative PCR Nucleic Acids Res. 2002 May 15;30(10):e47. doi: 10.1093/nar/30.10.e47. ... Here we present a primer pair that eliminates this problem, allowing simple and rapid measurement of telomeres in a closed tube ... This assay will facilitate investigations of the biology of telomeres and the roles they play in the molecular pathophysiology ...
  • In contrast, telomeres from sperm DNA did not decrease with age of the donor, suggesting that a mechanism for maintaining telomere length, such as telomerase expression, may be active in germ-line tissue. (pnas.org)
  • We also found that fibroblasts from Hutchinson-Gilford progeria donors had short telomeres, consistent with their reduced division potential in vitro. (pnas.org)
  • This lengthening did not occur in nullizygotes, and short telomeres inherited from mTert null parents were rescued only in heterozygous progeny. (biologists.org)
  • Here, a germline missense mutation of MDM4 , a negative regulator of p53, was found in a family with features suggestive of dyskeratosis congenita, e.g., bone marrow hypocellularity, short telomeres, tongue squamous cell carcinoma, and acute myeloid leukemia. (sciencemag.org)
  • OA and OP have been characterized as age‑related diseases and have been associated with telomere shortening and altered telomerase activity (TA). (spandidos-publications.com)
  • We studied Tert expression patterns, telomerase activity, cytosolic reactive oxygen species (ROS) production, and telomere length in fresh oocytes from young versus reproductively-aged female mice retrieved from oviducts at 14 h post-human chorionic gonadotropin (hCG), in vivo or in vitro postovulatory-aged mouse oocytes at 23 h post-hCG. (biomedcentral.com)
  • Telomerase activity was measured by a telomeric repeat amplification protocol assay, while telomere length was measured by Q-PCR and quantitative fluorescence in situ hybridization analyses. (biomedcentral.com)
  • Long-term adverse effects of low telomerase activity and increased ROS exposure are likely associated with telomere shortening in oocytes from reproductively-aged female mice. (biomedcentral.com)
  • In patients who have received hematopoietic stem cell transplantation (HSCT), the telomere length and the telomerase activity of the engrafted donor cells have a significant influence on HSCT outcomes. (biomedcentral.com)
  • Because clinical observations suggest that leukemic cells accumulate at different rates, we measured telomere length and telomerase activity in B-CLL cells to distinguish differences in cellular replication. (elsevier.com)
  • Leukemic cells of the immunoglobulin V gene mutation subgroups differ in telomere length and telomerase activity. (elsevier.com)
  • B lymphocytes from the subgroup with poor outcome and with limited IgV gene mutations have uniformly shorter telomeres and more telomerase activity than those from the subgroup with better outcome and with considerable mutations. (elsevier.com)
  • Telomere addition by telomerase does not occur at every telomere in each cell cycle, yet an equilibrium average length is often maintained, with longer telomeres exhibiting a decreased propensity for elongation compared with shorter telomeres ( Hug and Lingner, 2006 ). (biologists.org)
  • Recombination at mammalian telomeres: an alternative mechanism for telomere protection and elongation. (ox.ac.uk)
  • Here we discuss the way in which HR contributes to telomere protection and elongation in mammalian cells. (ox.ac.uk)
  • Est1A/SMG6 controls telomere elongation by mediating telomerase recruitment. (uni-ulm.de)
  • Moreover, we found that TERT localization at telomeres is maintained all through spermatogenesis as a structural component without affecting telomere elongation. (unipv.it)
  • Because we had previously shown that telomeres, the terminal guanine-rich sequences of chromosomes, shorten throughout the life-span of cultured cells, we wished to determine whether variation in initial telomere length would account for the unexplained variation in replicative capacity. (pnas.org)
  • In this thesis, the levels of these modifications were studied in telomeric chromatin and in the telomere adjacent chromatin of the short arm of the human sex chromosomes (XpYp) in a panel of six human cell lines utilising different telomere maintenance mechanisms. (le.ac.uk)
  • Telomeres are nucleoprotein complexes at the ends of chromosomes and consist of tandem arrays of short repetitive sequences (TTAGGG in humans) and a set of specialized proteins ( 1-3 ). (aacrjournals.org)
  • As caps at the ends of chromosomes, telomeres play a critical role in protecting chromosomes from degradation, end-to-end fusion, abnormal recombination, and other detrimental chromosomal events ( 4, 5 ). (aacrjournals.org)
  • Telomeres and telomere-associated proteins maintain genome stability by protecting the ends of chromosomes from fusion and degradation. (biomedcentral.com)
  • The telomeres are specific nucleoprotein structures at the ends of eukaryotic chromosomes which maintain genome stability by protecting chromosomes from end fusion and degradation. (biomedcentral.com)
  • Telomeres are ribonucleoprotein structures at the end of chromosomes composed of telomeric DNA, specific-binding proteins and noncoding RNA (TERRA). (unipv.it)
  • Recently, knockout mouse cell lines have indicated that epigenetic modifications associated with telomeric and subtelomeric chromatin, including DNA methylation, Histone 3 Lysine 9 (H31K9) trimethylation and Histone 4 Lysine 20 (H4K20) trimethylation, play an important role in influencing the choice of telomere maintenance mechanism. (le.ac.uk)
  • While telomeric DNA is mostly double-stranded, telomeres terminate with a single-stranded GT-rich 3′ overhang, known as G-tail. (prolekare.cz)
  • Telomere length was measured by quantitative polymerase chain reaction from blood and expressed as the amount of telomeric genomic DNA to the beta-globin gene (T/S ratio). (edu.au)
  • Importantly, our data show that telomere integrity is impacted by heat shock and that telomeric DNA damages are markedly enhanced in HSF1 deficient cells. (uclouvain.be)
  • Telomeric Repeat-Containing RNA (TERRA) and Telomerase Are Components of Telomeres During Mammalian Gametogenesis. (unipv.it)
  • While both TERRA levels and distribution would be regulated in a gender-specific manner, telomere-TERT co-localization appears to be regulated based on species-specific characteristics of the telomeric structure. (unipv.it)
  • Recently, a high-profile study reported a negative birth-cohort effect on leukocyte mean telomere length in human populations, namely the progressive loss of telomeric sequence between healthy human generations. (biomedcentral.com)
  • Many proteins cooperate to establish and maintain telomere integrity and replication in mammals ( de Lange, 2005 ). (biologists.org)
  • In mammalian cells, double-stranded DNA (dsDNA)-specific telomere binding proteins are encoded by TRF1 and TRF2 and a single-stranded DNA (ssDNA)-specific telomere binding protein is encoded by POT1, and together with RAP1, TIN2 and TPP1, they form a telomere protection complex known as "shelterin" [4] . (prolekare.cz)
  • Significantly shortened telomeres, activation of telomerase, and altered expression of telomere-associated proteins are common features of various hematologic malignancies and are related with progression or chemotherapy resistance in these diseases. (biomedcentral.com)
  • cells defective in the recombinational repair proteins RAD51D or RAD54 exhibit telomere shortening and end-to-end chromosome fusions. (ox.ac.uk)
  • Telomeres are the protective caps of eukaryotic chromosome ends and are known to shorten in the dividing cells of somatic tissues of higher animals during aging, in contrast to telomeres in the germline, which have been thought to remain stable in a species. (biomedcentral.com)
  • When telomere lengths become critically short, the process of cell senescence is initiated, resulting in cell-cycle arrest or apoptosis in normal cells ( 9 ). (aacrjournals.org)
  • As telomere shortening in cultured somatic cells triggers replicative senescence, telomere shortening in oocytes during reproductive and postovulatory aging may predict developmental competence. (biomedcentral.com)
  • The mouse has proven to be a valuable model with which to dissect the role of telomere attrition in cellular proliferation and disease. (biologists.org)
  • Importantly, our longitudinal analyses revealed a positive relationship between initial TL and telomere attrition rate within individual lizards i.e. lizards with short initial telomeres were subjected to reduced telomere attrition rates compared to lizards with long initial TL. (wildgenesgroup.com)
  • It has been suggested that there is a relationship between telomere attrition in the early stages of carcinogenesis and activation of the DNA damage response machinery. (elsevier.com)
  • Recent work has linked psychological stress with premature cellular aging as indexed by reduced leukocyte telomere length. (cardiffmet.ac.uk)
  • Yet, several research groups have reported the surprising findings of longer telomeres in the germ cells of older men, which translated into longer leukocyte telomere length in their offspring. (biomedcentral.com)
  • Telomerase replenishes telomere sequences that are lost during end processing and replication through its telomere polymerisation activity at single-stranded guanine (G)-rich overhangs, conferred by the telomerase reverse transcriptase (TERT) and the reverse transcription of an internal RNA component (TER, or TERC) ( Hug and Lingner, 2006 ). (biologists.org)
  • However, evidence suggests that elongated telomeres can prevent loss of subtelomeric DNA methylation associated with replication in normal human cells. (le.ac.uk)
  • Thus, we investigated how loss of Poz1, Rap1 and Taz1 affects cell cycle regulation of Ccq1 Thr93 phosphorylation and telomere association of telomerase (Trt1 TERT ), DNA polymerases, Replication Protein A (RPA) complex, Rad3 ATR -Rad26 ATRIP checkpoint kinase complex, Tel1 ATM kinase, shelterin subunits (Tpz1, Ccq1 and Poz1) and Stn1. (prolekare.cz)
  • In somatic cells under normal physiologic conditions, telomeres are progressively eroded by about 30 to 200 bp because of the end-replication problem during each mitotic cell division ( 6 ). (aacrjournals.org)
  • Dyskeratosis congenita is a cancer-prone inherited bone marrow failure syndrome caused by telomere dysfunction. (sciencemag.org)
  • Our data indicate that a germline activation of the p53 pathway may cause telomere dysfunction and point to polymorphisms affecting this pathway as potential genetic modifiers of telomere biology and bone marrow function. (sciencemag.org)
  • Given that telomere shortening in Est1 knockout tissues is not associated with telomere dysfunction or an activation of DNA damage checkpoints, these results suggests that loss of NMD function leads to selective toxicity in HSCs but not in other stem cell compartments. (uni-ulm.de)
  • Human telomeres can be maintained by the enzyme telomerase, which catalyses the addition of telomere repeats, or by the Alternative Lengthening of Telomeres (ALT) mechanism, which is recombination based. (le.ac.uk)
  • This review discusses the role of telomeres and telomerase in OA and OP pathologies and focuses on the usability of telomere length (TL) and the rate of telomere shortening as potential disease biomarkers. (spandidos-publications.com)
  • The shelterin complex in fission yeast consists of Taz1 (TRF1/TRF2 ortholog) that specifically recognizes double-stranded telomeres, the G-tail binding protein Pot1, Tpz1 (TPP1 ortholog), Rap1, Poz1 and Ccq1. (prolekare.cz)
  • While TERT maintains telomere length under standard conditions, telomeres under increased stress shorten as fast as in cells without active telomerase. (fightaging.org)
  • We show that prolonged mTert heterozygosity (for greater than ten generations) did not elicit disease, even upon heterozygote interbreeding, and that telomeres reset to wild-type lengths. (biologists.org)
  • Finally, telomere lengths were long in 38.9% and very short in 38.9% of breast carcinomas (P = 0.0087 for comparisons with preneoplastic lesions). (elsevier.com)
  • Welders had marginally shorter average telomere lengths than the administrative workers (p=0.058). (ncku.edu.tw)
  • Studies in fission yeast have previously identified evolutionarily conserved shelterin and Stn1-Ten1 complexes, and established Rad3 ATR /Tel1 ATM -dependent phosphorylation of the shelterin subunit Ccq1 at Thr93 as the critical post-translational modification for telomerase recruitment to telomeres. (prolekare.cz)
  • These analyses established that fission yeast shelterin maintains telomere length homeostasis by coordinating the differential arrival of leading (Polε) and lagging (Polα) strand DNA polymerases at telomeres to modulate Rad3 ATR association, Ccq1 Thr93 phosphorylation and telomerase recruitment. (prolekare.cz)
  • Mutations that affect shelterin or telomerase function in mammalian cells could lead to diseases that show premature aging due to depletion of the stem cell population, highlighting the importance to understand the regulatory mechanisms that ensure stable telomere maintenance [5] . (prolekare.cz)
  • Identification of a telomere protection complex that closely resembles mammalian shelterin [6] , coupled with the amenability to detailed genetic and molecular analysis, have made fission yeast Schizosaccharomyces pombe an attractive model organism to study telomere maintenance [7] . (prolekare.cz)
  • Telomerase is recruited to the telomere via its interaction with shelterin. (biomedcentral.com)
  • Here, we provide evidence that both TERRA and the telomerase enzymatic subunit (TERT) are components of telomeres in mammalian germ cells. (unipv.it)
  • In eukaryotic cells, dynamic cell cycle-regulated protein-DNA complexes formed at telomeres play key roles in the maintenance of genome stability [1] , [2] . (prolekare.cz)
  • Thus, gradual telomere erosion in the presence of telomerase may enable subsequent telomere extension, similar to that described in budding yeast. (biologists.org)
  • for example, life stress and oxidative stress may accelerate telomere shortening ( 7, 8 ). (aacrjournals.org)
  • The relative length of each specific telomere is defined in the zygote, determined by inherited factors, and maintained throughout life, but average telomere length shortens with increasing age ( 24-26 ). (aacrjournals.org)
  • This study aimed to ascertain the mechanisms underlying altered telomere biology in mouse oocytes during reproductive and postovulatory aging. (biomedcentral.com)
  • Understanding the mechanisms by which HR promotes telomere maintenance has important implications for genomic stability and tumorigenesis. (ox.ac.uk)
  • Context: Chronic psychological stress has been associated with shorter telomeres in some studies, but the underlying mechanisms are poorly understood. (cardiffmet.ac.uk)
  • the murine genes are hereafter referred to as mTerc and mTert , respectively), the eventual loss of telomere DNA leads to end-to-end fusions and defects in many tissues and progenitor cell compartments, including the blood, skin, intestine and germline ( Blasco, 2005 ). (biologists.org)
  • We found that TERRA co-localizes with telomeres during mammalian meiosis and that its expression progressively increases during spermatogenesis, until the beginning of spermiogenesis. (unipv.it)
  • Our results represent the first evidences of co-localization between telomerase and telomeres during mammalian gametogenesis. (unipv.it)
  • Transplantation-related factors should be taken into consideration because of their impacts on telomere homeostasis. (biomedcentral.com)
  • Additionally, the level of chromatin modifications associated with binding of 53BP1 was not affected by the telomere maintenance mechanism used in human cell lines. (le.ac.uk)
  • In addition, both Cdc13 and Stn1 were found to be involved in the regulation of telomere length, mutations in STN1 or CDC13 conferring an increase in telomere size. (scripps.edu)
  • Here, we observe that the function of HSF1 extends to telomeres and identify subtelomeric DNA as a new genomic target of HSF1. (uclouvain.be)
  • P = 0.004), indicating that cell strains with shorter telomeres underwent significantly fewer doublings than those with longer telomeres. (pnas.org)
  • P = 0.025), consistent with the correlation of this variant allele with longer telomeres. (aacrjournals.org)
  • Longer telomeres in the somatic cells of an individual have been regarded as a marker of youth and biological fitness within a population. (biomedcentral.com)
  • A mouse model recently suggested that p53 regulates telomere metabolism, but the clinical relevance of this finding remained uncertain. (sciencemag.org)
  • Autosomal dominant mutations in telomere-associated factors elicit a disease known as dyskeratosis congenita (DKC), and patients suffer proliferative abnormalities associated with telomere erosion. (biologists.org)
  • Similarly, the reported increase in the variability of telomere length in the spermatozoa of older men [ 5 ] can be easily explained by the lifelong mitotic activity of several populations of germ stem cells, which are exposed to environmental insults and subject to all kinds of errors, analogous to the increasing burden of acquired mutations in the spermatocytes of aging men. (biomedcentral.com)
  • This is in place of the more expected path of undoing ongoing telomere shortening by adding extra repeat sequences to the end of the telomeres - that being the better understood function of telomerase. (fightaging.org)
  • You might recall that researchers have put forward evidence to suggest that telomere shortening is caused by accumulated damage to mitochondrial DNA - essentially collapsing two areas of intense interest for gerontologists down to one root cause, if confirmed. (fightaging.org)
  • We also know that progressive telomere shortening is tied to aging and age-related disease, and a number of different groups are working on strategies to safely lengthen telomeres. (fightaging.org)
  • Telomerase is a ribonucleoprotein that counteracts telomere shortening and can immortalise human cells. (fightaging.org)
  • So, poorly functioning mitochondria lead to telomere shortening, and telomerase somehow improves mitochondrial function to prevent that shortening. (fightaging.org)
  • A number of studies have demonstrated that telomere shortening may contribute to OA and OP as an epigenetic factor. (spandidos-publications.com)
  • We further investigated how telomere shortening, caused by trt1Δ or catalytically dead Trt1-D743A, affects cell cycle-regulated telomere association of telomerase and DNA polymerases. (prolekare.cz)
  • Telomere shortening is associated with the risk of many aging-related diseases. (aacrjournals.org)
  • Telomere shortening has been associated with aging and many aging-related diseases including cancer ( 6 , 10-12 ). (aacrjournals.org)
  • In tumor cells, the shortening of telomeres length is accelerated under the increased proliferation pressure. (biomedcentral.com)
  • Cre-mediated deletion of mEst1A in adult mice led to telomere shortening in small intestine comparable to the first generation of TERC deficient mice. (uni-ulm.de)
  • The present study aimed to evaluate associations between the occupational exposure of metals and oxidative damage and telomere length shortening in workers involved in the manufacture of fitness equipment. (ncku.edu.tw)
  • These observations suggest that telomere length is a biomarker of somatic cell aging in humans and are consistent with a causal role for telomere loss in this process. (pnas.org)
  • In normal somatic cells, the length of the telomeres gradually becomes shortened with cell division. (biomedcentral.com)
  • No evidence of association was seen for adult FEV1 or FVC, or any childhood spirometric index after adjustments.Conclusion:Shorter telomere length showed moderate associations with poorer airflow parameters, but not vital capacity (lung volume) in mid-life adults. (edu.au)
  • Relative telomere length (RTL) was remarkably shorter in oocytes from reproductively-aged females compared to oocytes from young females. (biomedcentral.com)
  • Subtelomeric DNA methylation in the mouse has been shown to have a dynamic relationship with telomere length. (le.ac.uk)
  • Telomeres play a critical role in maintaining genome integrity. (aacrjournals.org)
  • Telomeres in preneoplastic lesions were more frequently shorter than those in normal tissues (P = 0.0116). (elsevier.com)